The picture theory of seven pathways associated with COVID-19 in the real world

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Kast, Badar A. Kanwar, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3849399/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Sep, 2024 Read the published version in Virology Journal → Version 2 posted You are reading this latest preprint version Show more versions Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated diseases. Interactions between the host and virus govern induction, resulting in multiorgan impacts. In 2021, as normal life was challenging during the pandemic era, we analyzed SCI journals according to L. Wittgenstein's Tractatus Logi-co-Philosophicus. The pathophysiology of coronavirus disease 2019 (COVID-19) involves the following steps: 1) the angiotensin-converting enzyme (ACE2) and Toll-like receptor (TLR) pathways: 2) the neuropilin (NRP) pathway, with seven papers and continuing with twenty-four: 3) the sterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein 1 (SAMHD1) tetramerization pathway, with two papers and continuing with twelve: 4) inflammasome activation pathways, with five papers and continuing with thirteen: 5) the cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) (cGAS–STING) signaling pathway, with six papers and successful with eleven: 6) the spike protein pathway, with fourteen and continuing with twenty-three: 7) the immunological memory engram pathway, with thirteen papers and successive with eighteen: 8) the excess acetylcholine pathway, with three papers and successful with nine. We reconfirmed that COVID-19 involves seven (1-7) pathways and a new pathway involving excess acetylcholine. Therefore, it is necessary to therapeutically alleviate and block the pathological course harmoniously with modulating innate lymphoid cells (ILCs) if diverse SARS-CoV-2 variants are subsequently encountered in the future. ACE2 cGAS–STING Immunologic engram Inflammasome NLRP3 SAMHD1 SARS-CoV-2 Spike protein TLR4 Acetylcholine Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated diseases. The symptoms of these patients are distributed across multiple geographical limits. Interactions between the host and virus govern induction, resulting in various consequences 1 . Blood levels of cytokines during infection with COVID-19 are characterized by distinct C-reactive protein (CRP), interleukin-6 (IL-6), or triglyceride levels and significantly increased circulation 2 3 4 5 6 . The pathophysiologic mechanisms include direct toxicity through virus-dependent means, including invasion of alveolar epithelial and endothelial cells by SARS-CoV-2 and microvascular endothelial injury. Other virus-induced indirect conditions might be encountered during infection in the elderly with dementia drugs, such as immunological damage by suppressed muscarinic receptor and a dysregulated hyperinflammatory state, including perivascular inflammation and hypercoagulability with resultant thrombotic occlusions, effects on the renin-angiotensin-aldosterone system (RAAS), and the endothelium as well as maladaptation to the angiotensin-converting enzyme 2 (ACE2) pathway 7 . Hypercoagulability and hyperinflammation may favor stroke via microvascular circulation abnormalities, microthrombus formation, and multifocal lesions 8 . This pathological combination contributes to the breakdown of the endothelial–epithelial barrier 9 . Seven pathways and a novel excess acetylcholine pathway describe acute kidney injury, hepatic, cardiac, neurological, and gastrointestinal injury: acute coronary syndrome, myocarditis, arrhythmia, Takotsubo cardiomyopathy, stroke, encephalopathy, anosmia, transaminitis, diarrhea, nausea, vomiting, and anorexia 10 . We have vigilantly monitored for underlying conditions. Our study describes the important molecular pathways associated with SARS-CoV-2 infection and provides detailed descriptions of pathological metabolic pathways based on eight tracks. Results For 2023, two years after 2021, we checked the final experimental results and found that they matched precisely within the seven pathways. The experimental results for 2022 and 2023 are underlined along with the cited papers. Papers published before 2020 were excluded from the analysis. Only papers published from 2020 to 2024 are described (Table 1). 1. Of the eight papers cited on the ACE2 and TLR pathways, five were used, and three were not used. Six papers were added to the last version. Nineteen papers were added that described ACE2, TLRs, and inflammasome activation. Six papers were rediscovered between 2022 and 2023. 2. In the neuropilin‑1 pathway, all seven cited papers were used. Twenty-four papers were successive. Papers 54 and 58 were added while explaining the engrams. These findings provide insight into the distribution of NRP1 in brain cells. It was rediscovered by seven papers between 2022 and 2023. 3. In the SAMHD1 tetramerization pathway, two papers were used. Twelve papers were successive. Papers 64 and 81 were added while explaining the characteristics of the inflammatory response and IFN action caused by the spike protein. These findings were rediscovered by seven papers dated from 2022-2023. 4. In the inflammasome activation pathway, three of the five cited papers were still used. Paper 204 was not used, and paper 117 was used to explain why the spike protein activates the inflammasome. Thirteen papers were successive to the last version, and the findings were rediscovered by six papers from 2022-2023. 5. In the cGAS–STING signaling pathway, three of the six cited papers were still used. Papers 206 and 207 were not used, and paper 119 went on to explain the generation of an immune response by the spike protein. Eleven papers were published successively, and the findings were rediscovered by five papers from 2022-2023. 6. In the spike protein pathway, seven out of fourteen papers were continuously used. Papers 210, 211, 212, and 213 were not used; paper 16 went on to explain the mechanism by which ACE2 activates the inflammasome; and papers 64 and 81 went on to describe SAMHD1, which prevents virus invasion. Twenty-three papers were successive, 117 of which explained the inflammasome and 119 of which explained the cGAS–STING inflammasome; these findings were rediscovered by eight papers from 2022-2024. 7. In the immunological memory engram pathway, nine out of the thirteen papers were continuously used. Papers 214 and 215 were not used, and papers 54 and 58 were used to explain the clinical correlation between NRP1 in the brain and ARDS in the lung. Eighteen papers were published, and the findings were rediscovered by five papers published between 2022 and 2024. 8. Three papers were added to the excess acetylcholine pathway in 2022, and new results were rediscovered by nine papers from 2022-2023. 1 . ACE2 and TLR pathways The life cycle of SARS-CoV-2 begins after binding to ACE2 in the epithelium of the oral mucosa, lung, heart, and kidney, and the expression of ACE2 increases with age 11 12 . Smoking affects ACE2 expression and induces mineral dust‑induced gene (MDIG) expression, which alters the transcription of several essential proteins implicated in exacerbating COVID-19 13 14 . This type of epigenetic gene expression alters gene locus function without changing the underlying DNA sequence. Instead, it relies on posttranslational chemical changes in chromatin, RNA, and DNA. These changes include acetylation, methylation, phosphorylation, ubiquitination and SUMOylation. These changes are linked to genotype and phenotype 15 . The interaction of ACE2 with the SARS-CoV-2 spike protein (SP) in tiny numbers of embryonic-like stem cells (VSELs) and hematopoietic stem cells (HSCs) activates the NLR family PYRIN domain containing-3 (NLRP3) inflammasome. The exposure of human umbilical cord blood (UCB)-purified VSELs to recombinant SP can lead to the upregulation of NLRP3 mRNA expression 16 . Human VSELs in adult tissues can be damaged by SARS-CoV-2, which has downstream and subsequent effects on tissue/organ regeneration 16 . SARS-CoV-2 activates mitochondrial reactive oxygen species (ROS) production and glycolytic shift. SP alone can damage vascular endothelial cells by downregulating ACE2 and inhibiting mitochondrial function 17 . ACE2 and Toll-like receptor 4 (TLR4, CD284) on the cell surface belong to the pattern recognition receptor (PRR) family. ACE2 and TLR4 are highly expressed in hematopoietic stem and progenitor cells. These cells are highly susceptible to SP. ACE2 and TLR4 produce inflammatory cytokines and activate innate immune responses. Erythroid precursor cells (from CD 34 + ) differentiate into red blood cell (RBC) precursors and subsequently express ACE2. The SARS-CoV-2 SP interacts with RBC precursors, leading to dysregulation of hemoglobin and degradation of Fe-heme 18 19 . Blocking the interaction of SP with cell surface-expressed ACE2 and TL4 decreased the activation of the downstream mediator of NLRP3, caspase-1. This suppression was even more noticeable after blocking the interaction of the SP with both receptors. Exposure to SP upregulates the expression of proteins participating in the positive stimulation of the TLR4 signaling pathway 18 . The SP has been proposed to have the most substantial protein‒protein interaction with TLR4. TLR2 and TLR4 are expressed intracellularly in dendritic, epithelial, and endothelial cells 20 21 . The molecular influence of TLR4 is understood as a prime regulatory factor associated with immunity 22 . TLR4 mediates anti-gram-negative bacterial immune responses by recognizing lipopolysaccharide (LPS) from bacteria 23 . Staphylococcus aureus triggers an inflammatory response in innate immune cells via TLR4 and the inflammasome 24 . SARS-CoV-2 infection results in viral sepsis and provokes an antibacterial-like response at the very early stage of infection via TLR4 25 ( Fig. 1 ). TLRs are a class of membrane pattern recognition receptors that detect microbes on the cell surface and in the cytoplasm, and a cytokine surge is induced by TLRs, mainly through the activation of TLR3, TLR4, TLR7, and TLR8 26 . Subunit 1 of the SARS-CoV-2 spike protein (S1) induces sickness behavior and a subacute neuroinflammatory response for approximately 24 hours and a chronic neuroinflammatory response for approximately 7 days. Moreover, S1 directly induces a proinflammatory response in primary microglia and activates TLR4 signaling 27 . Neuroinflammation induced by microglia is mediated through the activation of nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) due to TLR2 and TLR4 activation 26 27 28 . TLR4 has been shown to play a role in mediating the neurotoxicity induced by α-synuclein (α-Syn) oligomers. Misfolded α-Syn induces inflammatory responses; however, α-Syn uptake is independent of TLR4. Furthermore, extracellular α-Syn can activate the proinflammatory TLR4 pathway in astrocytes 29 . The interaction between the SARS-CoV-2 SP and TLR4 can trigger an intracellular TLR4 signaling cascade. The NF-κB-mediated transcriptional activation of specific genes induces the release of proinflammatory cytokines, which can damage neurons and pathologically modify α-Syn 30 . The final sequence of NF-κB activation involves a range of cytokine receptor- and TLR-mediated signaling cascades. SARS-CoV-2 induces TLR4-mediated NF-κB activation, and erythroreticulum (ER) stress induces NF-κB activation and the production of immature IL-1β (pro-IL-1β) 31 . 2. The neuropilin‑1 pathway Neuropilin-1 (NRP1) is a pleiotropic single-transmembrane coreceptor for class 3 semaphorins and vascular endothelial growth factors. Along with ACE2, NRP1 facilitates the entry of SARS‑CoV‑2 into host cells. NRP1 is a highly conserved transmembrane receptor lacking a cytosolic protein kinase domain 32 33 . In combination with host transmembrane protease serine 2 (TMPRSS2), SARS-CoV-2 uses the ACE2 receptor for cell entry, which cleaves the viral spike glycoprotein 34 35 . The expression of ACE2 and NRP1 with TMPRSSs has been observed in various human tissues and organs, thus facilitating viral activation and representing the essential host factors for SARS-CoV-2 pathogenicity. These viruses contribute to the tropism of SARS-CoV-2 in diverse tissues and organs and its related symptoms . NRP1 is expressed in all vertebrates. NRP1 is the primary coreceptor for ACE2. NRP1 contributes to the primary tissue or organ tropism of SARS-CoV-2. NRP1 and 2 are involved in angiogenesis, axon control, cell proliferation, immune function, neuronal development, and vascular permeability because NRP1 is a coreceptor for vascular endothelial growth factors 36 . NRP1 plays a complex role in the secondary CD8+ T-cell response to control VRDs and tumors 37 . A complete understanding of NRP1 or NRP2 and its associated mechanical pathways will facilitate understanding of SARS-CoV-2 infectivity and improve patient treatments; however, ACE2 is the primary receptor for entry of SARS-CoV-2 into cells (Fig. 2) . The genetic susceptibility locus in respiratory failure patients with COVID-19 is located on chromosomes 3p21.31 and 9q34.2 and is related to severity; the 3p21.31 gene cluster can be found on chromosome 3 38 . The risk locus is inherited from Neanderthals, which are segmented by a genomic size of approximately 50 kilobases, and there is no evidence that genetic haplotypes progressed from Neanderthals into African populations 31 . According to the protein docking crystal structures, the receptor binding domain (RBD) of the SARS-CoV-2 spike protein has a potentially high affinity for dipeptidyl peptidase-4 (DPP4). The present genetic variants from a Neanderthal heritage plant were located in six genes on chromosome 3p21.31, which is in the proximal promoter region of DPP4. The DPP4 gene encodes the enzyme dipeptidyl peptidase IV. Dipeptidyl peptidase IV serves as a receptor for MERS-CoV 39 , but a genetic variant in the promoter region of the DPP4 gene has been shown to double the risk of developing critical COVID-19 pathogenesis. Moreover, DPP9, a homolog of DPP4, was significantly associated with severe COVID-19. These findings suggested a potential role for DPP4 in COVID-19 40 . A haplotype on chromosome 12 from Neanderthals is associated with an approximately 22% decrease in the relative risk of developing severe illness 41 . MDIGs are mainly responsible for the expression of inflammatory cytokines, the critical component of the inflammasome, and most of the genes involved in glycan metabolism for hyaluronan generation and glycosylation. MIDGs are crucial determinants of viral infection and cytokine storms 42 . MDIG is an environmentally induced lung cancer oncogene whose entry into MDA-MB-231 and A549 cells depends on NRP1 and NRP2 expression in the cell membrane 42 . MDIG is also an essential regulator of NRP1 and NRP2. In MDIG knockout cells, researchers observed strong H3K9me3 and H4K20me3 upstream of the DPP4 gene from the Neanderthal haplotype region at chromosome 3p21.31 and chromosome 2q24.2 on the proximal promoter region of DPP4, which is another Neanderthal variant gene 42 . Moreover, these effects are attributable to pulmonary fibrosis in some COVID-19 survivors. Among patients with a history of environmental exposure, MDIG plays a critical role in preventing SARS-CoV-2 infection and reducing the severity of COVID-19. The MDIG-dependent expression of NRP1 or NRP2 enhances SARS-CoV-2 infection in cells with lower ACE2 expression 42 . Knockout of MDIG does not affect the enrichment of the repressive histone trimethylation markers H3K9me3, H3K27me3, or H4K20me3 on the protective Neanderthal haplotypes on chromosome 12, which reduces the risk of exacerbating COVID-19 41 . NRP1 is a tissue-specific marker of lung 2 ILC2s and is induced postnatally and sustained by lung-derived transforming growth factor-β1 (TGFβ1). TGFβ1–NRP1 signaling enhances ILC2 functions and type 2 immunity, suggesting that NRP1 is a tissue-specific regulator of lung-resident ILC2s and that the NRP1 regulator is a potential therapeutic agent for pulmonary fibrosis 43 . In addition, NRP1 and NRP2 support competent viral entry into host cells in the lung. MDR complex access to two additional cell lines (MDA-MB-231 and A549) depends on NRP1 and NRP2. Moreover, MDIG has a role in preventing SARS-CoV-2 infection and reducing the severity of COVID-19 in patients who are experiencing environmental exposure to toxins. These effects explain the observed pulmonary fibrosis in some COVID-19 survivors; MDIG-dependent expression of NRP1 or NRP2 increases SARS-CoV-2 infection despite reduced ACE2 expression 42 . ILC2s are involved in virus-induced exacerbation of airway inflammation and are critical in pulmonary fibrosis and autoimmune disease 44 45 . Human ILC2s are flexible and adapt to the cytokine microenvironment by changing cytokine outputs to meet existing requirements 46 . ILC2s and eosinophils play vital roles in pulmonary arterial hypertrophy 47 . Group 3 ILCs (ILC3s) produce greater amounts of cytokines than ILC3s that do not express NRP1. NRP1 + ILC3s are present in fetal tissues and ectopic lymphoid aggregates and play a role in inflammation and vascularization 48 . SARS-CoV-2 targets ciliated cells in the respiratory mucosa, but in the olfactory mucosa, the primary target is nonneuronal sustentacular cells. NRP1 is expressed in olfactory‑related neuronal regions 49 50 . Compared with other brain regions, SARS-CoV-2 may exhibit tropism to the brainstem, which has relatively high expression of the ACE2 receptor 32 33,51 52 . The recognized pathways involve transsynaptic transfer via peripheral, olfactory, or cranial nerves and blood‒brain barrier (BBB) penetration from the systemic circulation to invade the brainstem 51 52 53 . The recognized pathways invade the brainstem and involve transsynaptic transfer via peripheral, olfactory, or cranial nerves ( Fig. 3 ). Clinically, COVID-19-related acute respiratory distress syndrome (ARDS) is characterized by relatively preserved aeration on chest computed tomography (CT) despite severe respiratory hypoxemia. However, this early, high-compliance phenotype can develop into a low-compliance phenotype with poor aeration as L-type, characterized by low elastance, high compliance, and preserved aeration; and H-type, characterized by high elastance, low compliance, and poor aeration 54 . Patients with cryptococcus-associated immune reconstitution inflammatory syndrome can suffer from pulmonary dysfunction caused by T-cell-driven neurodegeneration in the vital medullary nucleus responsible for respiratory control 55 56 . The paralysis of the pre-Bötzinger complex on the medullar oblongata in the brainstem might affect L-type ARDS and COVID-19-associated fatality 57 . NRP-1 might induce the tropism of SARS-CoV-2 in the brainstem 51 57 58 . 3. The SAMHD1 tetramerization pathway VRDs produce interferon (IFN)-1, which exacerbates their pathological course, but interferon treatment reduces inhibitory M2 muscarinic receptor function 59 . The genesis of the acetylcholine (ACh) receptor requires interferon 60 . Muscarinic and nicotinic ACh receptors regulate immune function 61 . The sterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein 1 (SAMHD1) operate at stalled replication forks to prevent the induction of IFN, a significant regulator of deoxynucleotide triphosphate (dNTP) concentrations in human cells 62 . The concentrations of dNTPs, substrates for DNA-polymerizing enzymes, are limited in cells. However, SAMHD1 is a deoxyribonucleotide triphosphate triphosphohydrolase (dNTPase) that cleaves dNTPs to deoxynucleosides and triphosphates. The induction of SAMHD1 in differentiated cells requires low levels of dNTPs in nonproliferating cells to mediate DNA repair and maintain mitochondria. High dNTP levels can cause problems in maintaining mitochondrial function, which might occur in Aicardi–Goutières syndrome (AGS) patients. This genetic inflammatory encephalopathy resembles congenital viral infections and certain autoimmune disorders. AGS mutations in the SAMHD1 gene reduce catalytic activity or allosteric activation by dGTP. They also increase intracellular dNTP levels. These mutations may contribute to the dysfunctional differentiation of innate immune cells. The phenotype of SAMHD1 mutations is consistent with that of AGS, which increases dNTP levels. This could lead to a more robust viral infection because of the loss of the dNTP triphophohydrolase activity of SAMHD1. Viruses can replicate their viral genome with their polymerase 63 . Elevated intracellular levels of dNTPs are biochemical markers of cancer cells. Many multifunctional dNTPase and SAMHD1 mutations have been reported in various cancers. The SAMHD1 R366C/H mutant has been found in colon cancer and leukemia, as shown in Supplemental Fig. 1 of Supplement 1 64 . R366C/H mutants retain dNTPase-independent functions, such as mediating dsDNA break repair, interacting with C-terminal binding protein 1 interacting protein (CtIP) and cyclin A2, and suppressing innate immune responses. The SAMHD1 R366 mutation does not alter the cellular protein levels of the enzyme but does inhibit the dNTPase activity and nucleotide density at the catalytic site on the X-ray structure. R366C/H does not restrict HIV-1 replication, which is a function of SAMHD1 that is dependent on the ability to hydrolyze dNTPs 64 . SAMHD1 negatively regulates the IFN-1 signaling pathway, and genetic loss of SAMHD1 elevates the innate immune response and IFN activation. The antiviral IFN responses induced by SAMHD1 suppressed SARS-CoV-2 replication and elevated cellular innate immunity 65 . Suppressing innate immune responses is essential for the survival of SARS-CoV-2 and HIV-1. Viral protein X (Vpx) performs several functions during infection, including downregulating SAMHD1 66 67 68 . This function of Vpx is conserved among the HIV-2/simian immunodeficiency virus (SIV) accessory protein Vpx 69 . The lentiviral Vpx variant suppresses SARS-CoV-2 RNA expression in primary human monocyte–derived macrophages 65 . Moreover, Vpx inhibits STING signalosomes and interferes with the nuclear translocation of NF-κB and the induction of innate immune genes 68 . Mutations in the Aicardi–Goutières syndrome protein SAMHD1 are implicated in the pathogenesis of chronic lymphocytic leukemia (CLL) and AGS. SAMHD1 has a target motif for cyclin-dependent kinase 1 (CDK1) ( 592 TPQK 595 : the CDK-targeted motif driving threonine 592 (T592) phosphorylation) 70 . CDKs are protein kinases that play key roles in cell division, transcriptional regulation, and viral infections 71 . SARS-CoV-2 infection triggers and redistributes cyclin D1 and D3 from the nucleus to the cytoplasm and subsequent proteasomal degradation. Cyclin D3 prevents the efficient incorporation of the envelope protein into virions during assembly. Its degradation during SARS-CoV-2 infection relieves cyclin interference with virion assembly 72 . Phosphorylation of SAMHD1 at residue T592 modulates the ability of SAMHD1 to block retroviral infection, but SAMHD1 can still decrease cellular dNTP levels 70 . A phosphomimetic environment mimics the phosphorylation of amino acid substitutions. A distinct negatively charged T592 phosphomimetic mutation generates electrostatic repulsive movement and reduces the stability of the SAMHD1 tetramer and the dNTPase activity of the enzyme. This repulsive electrostatic phosphorylation allosterically decreases dNTPase activity and may modify antiviral functions 73 . SAMHD1 forms tetramers of GTP, and all four dNTPs are controlled by the combined action and inactive apo-SAMHD1 interconverts between monomers and dimers. The binding of dGTP to four allosteric sites stimulates and causes a conformational change in the substrate-binding pocket, which results in a catalytically active tetramer 74 . The binding sites can adjust oligonucleotides instead of the allosteric activators GTP and dNTPs. The G-nucleotides containing oligonucleotides form a specific tetramer with mixed occupancy of the allosteric sites in the presence of GTP and dNTPs. Plastic and allosteric nucleic acid binding promotes the immunomodulatory effects of the antiretroviral activity of SAMHD1 75 . SAMHD1 can restrict retroviruses and protect cells from viral infections by catalyzing the hydrolysis of dNTPs in the dNTP pool. SAMHD1 depletes intracellular dNTPs into 20-deoxynucleoside and triphosphate products 70 76 . cell autonomous control of lentivirus infection in myeloid cells by SAMHD1 limits virus-induced production of IFNs and the induction of costimulatory markers. SAMHD1 autonomously controls viral infection through innate and adaptive immunity at the level of the infected cell. SAMHD1 limits lentivirus-induced IFN production in myeloid cells and reduces the induction of virus-specific cytotoxic T cells 77 . SAMHD1 mutations result in autoinflammatory AGS, and AGS secretes chronic IFN-I despite the absence of viral infections; moreover, this disease is characterized by early-stage brain disease 78 79 80 . SARS-CoV-2 encounters a response that requires the strong induction of a subclass of cytokines, including IFN-I, IFN-III, and a few chemokines 80 . The SAMHD1 tetramer structure could provide a mechanistic understanding of its rapid function in SARS-CoV-2 pathogenesis. SANHD1-deficient cells detect and activate IFN-I-mediated antiviral gene expression in HIV-1 cells via cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) (cGAS–STING) 79 . cGAS–STING is decreased during radiotherapy in cancer patients but promptly recovers after radiotherapy. SAMHD1, which suppresses viral replication and viral response genes, occurs more frequently in severe ventilation-associated COVID-19 patients than in nonventilated patients, and we observed important treatment-related alterations, specifically IFN-I responses. 81 . The degradation of SAMHD1 in human primary-activated/dividing CD4+ T cells, the increase in cellular dNTP levels, and the loss of dNTPase activity contribute to the increase in commonly observed dNTP levels 64 . SARS-CoV-2 aggravates a reaction in which SAMHD1 controls the innate immune response 65 . SAMHD1 in cells inhibits NF-κB activation and IFN-I induction 82 . Therefore, low levels of IFN-I could drive more severe SARS‐CoV‐2 infection 83 . 4. Inflammasome activation pathway The NLRP3 inflammasome contains NLRP3 as a sensor protein, ASC as an adaptor protein, and caspase-1 as an effector protein. The NLRP3 protein has three domains: 1. the pyrin domain (PYD), 2. the nucleotide-binding domain, and 3. the leucine-rich repeat domain. PYD interacts with apoptosis-associated speck-like protein with the caspase recruitment domain (ASC) PYD and subsequently promotes ASC oligomer formation. The ASC platform induces caspase-1 activation, which catalyzes the conversion of pro-IL-1β to mature IL-1β. NLRP3 deubiquitination and self-aggregation occur after ASC recruitment and oligomerization. Active caspase-1 cleaves pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18, respectively. Excessive IL-1β activates various signaling pathways, such as the NF-κB and Jun N-terminal kinase (JNK) signaling pathways, and as a result, it stimulates systemic inflammatory responses. IFN-α, IFN-β, IL-6, tumor necrosis factor (TNF), and TGFβ1 can lead to cytokine storms. The SARS-CoV-2 genome is enclosed by a nucleocapsid (N) protein in phospholipid bilayers. The membrane and envelope proteins are located among the SPs in the virus envelope. There are four main types of inflammasomes, NLRP1, NLRP3, NLRC4, and AIM2, which are classified after being regarded as distinct sensing proteins. Inflammasomes consist of at least three components: the inflammasome caspase (caspase-1, Caspase-4/11), an adapter molecule (ASC), and a sensor/receptor protein (NLRP1, NLRP3, NAIP1/2/5, NLRP12, AIM2, etc.) 84 . Active the NLRP3 inflammasome were found in tissues and peripheral blood mononuclear cells (PBMCs) from postmortem patients with moderate or severe COVID-19. The serum levels of IL-6, LDH, caspase-1, caspase-4/11, and IL-18 are correlated with disease severity. Moreover, higher Caspase-1, Caspase-4/11, and IL-18 levels are associated with poor clinical outcomes 85 . SARS-CoV-2 causes pyroptosis in human monocytes. Pyroptosis is associated with caspase-1, caspase-4/11, interleukin 1β (IL-1β), and gasdermin D expression and cytokine levels in primary monocytes 86 87 . SARS-CoV-2 engages in Caspase 4/11-mediated noncanonical activation of NLRP3 and contributes to COVID-19 exacerbation 87 . When recombinant baculoviruses displaying SP or nucleocapsid (N) protein were constructed and transfected into lung epithelial A549 cells and a spontaneously immortalized monocyte-like cell line (THP-1)-derived macrophages, the N protein triggered A549 cells to release more serum cytokines than did the SP 88 . Blocking the NLRP3 inflammasome reduces the cytokine storms and lung injury caused by SARS-CoV-2 infection. The N protein facilitated ASC oligomerization by increasing the interaction between NLRP3 and ASC. The N protein, NLRP3, and ASC form a complex and activate the NLRP3 inflammasome 89 . The SARS-CoV-2 ORF10 targets STING, attenuates the STING-TBK1 association, and impairs STING oligomerization, aggregation, and autophagy ( Fig. 4 ). It impairs cGAS–STING-TBK1 signaling and antagonizes STING-dependent IFN activation and autophagy 90 . ORF9b and nonstructural protein 7 (NSP7) antagonize the production of type I and III IFNs by targeting the retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5), TLR3-TIR-domain-containing adapter-inducing interferon-β (TRIF), and cGAS-STING signaling pathways 91 92 . The expression of NSP7 blocks innate immune activation and facilitates virus replication 93 . The detection of cytosolic DNA (cDNA) via the cGAS–STING axis induces a cell death program that initiates potassium efflux upstream of NLRP3. The combination of NLRP3 with cGAS-STING constitutes the primary inflammasome response during viral and bacterial infections in human myeloid cells and ameliorates the pathology of inflammatory conditions linked with cDNA sensing 94 . Microglial NLRP3 inflammasome activation is a major driver of neurodegeneration 95 96 97 ,, and purified SP activated the NLRP3 inflammasome in LPS-primed microglia in an ACE2-dependent manner 98 . In addition, mitochondrial antiviral signaling protein (MAVS) connects with NLRP3 and controls its inflammasome activity 99 . 5. cGAS–STING signaling pathway SARS-CoV-2, an RNA virus, activates the cDNA sensor cGAS–STING signaling in endothelial cells. The cGAS-STING pathway controls immunity to cDNA and drives aberrant IFN-I responses in patients with COVID-19 100 . Mitochondrial DNA is released and leads to IFN-I production. Blocking STING reduces severe lung inflammation, but a STING agonist also protects against SARS-CoV-2 infection 100 101 . cGAS catalyzes the conversion of cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) to cDNA. It triggers STING–tank-binding kinase 1 (TBK1)–interferon regulatory factor 3 (IRF3) signaling 102 . cGAS also appears in the nucleus, where cGAS in an inactive state is isolated from chromatin. Nuclear cGAS recruits protein arginine methyltransferase 5 (PRMT5) upon viral infection. In innate immunity, nucleus-localized cGAS interacts with PRMT5 to catalyze the symmetric dimethylation of histone H3 arginine 2 at IRF3-responsive genes, such as interferon beta 1 (IFNβ1) and interferon alpha 4 (IFNα4). As a result, PRMT5 facilitates IRF3 access 103 . Activated cGAS releases cGAMP, which binds to STING; thus, STING relocalizes and forms a clustered platform at the perinuclear Golgi. The kinase TBK1 phosphorylates IRF3, and IRF3 then enters the nucleus. Moreover, NF-κB triggers the expression of IFN-1 and proinflammatory cytokine genes 104 105 . Severe COVID-19-related inflammation is associated with excessive lung tissue damage and syncytial pneumocyte formation. Cultured epithelial cells expressing ACE2 and SP formed multinucleated syncytial cells. The fused cells exhibited DNA damage and micronuclei expressing cGAS-STING, which colocalized with and stimulated IFNs and IFN-stimulated genes 106 . The useful cellular functions of cGAS-STING are mediated by canonical and a few noncanonical pathways, but dysfunction of cGAS-STING-mediated cellular functions and noncanonical signaling underlie disease pathogenesis 107 . Activated STING triggers membrane permeabilization and thus lysosomal cell death. cGAS–STING–lysosomal cell death combined with NLRP3 ameliorates the pathology of inflammatory conditions through cytosolic DNA sensing 94 ( Fig. 5 ). The SARS-CoV-2 ORF3a can interact with STING. It selectively blocks cGAS–STING-induced autophagy by disrupting the STING-light chain 3 (LC3) interaction 108 . The pathway induces microglial activation to resolve inflammation in the brain. However, excessive engagement can lead to neuroinflammation and neurodegeneration 109 . cGAS–STING signaling is strongly related to the pathogenesis of neuroinflammation-driven disease progression 110 . A vast array of germline-encoded innate immune receptors, commonly known as PRRs, facilitate innate immune recognition. Due to cellular senescence, autoimmune disorders, and mitotic stress in cancers, cytosolic DNA levels increase. These events lead to the activation of cGAS–STING and the exacerbation of pathological courses 110 . 6. Spike protein pathway Glycoproteins are required for viral entry and fusion. The SP is a trimeric glycoprotein encoded by ORF2 in the viral genome. The membrane-distal S1 subunit and proximal S2 subunit in the virus envelope form homotrimers 111 . Glycoproteins derived from SARS-CoV-1, SACR-Co-V-2, human cytomegalovirus, and hepatitis C virus potentially trigger NLRP3 inflammasome activation and pyroptosis in THP-1 macrophages 112 113 . SP binding to ACE2 induces NF-κB activation and inflammation via ACE2 in endothelial cells 114 . The furin cleavage product of SP uses the vascular endothelial growth factor A (VEGF-A) binding site on NRP-1 as an entry point 115 . The SARS-CoV-2 SP S1 subunit activated the NF-κB and c-JNK signaling pathways. Furthermore, SP interacts with and activates TLR4 25 116 . SP induces neuroinflammation in BV-2 microglia, a microglial cell line derived from C57BL/6 mice. Immunofluorescence microscopy revealed increased TLR4 expression in BV-2 microglia when stimulated with S1 28 . After SARS-CoV-2 infection, the augmented immunogenicity of the SP results from macrophage reprogramming. SP-driven IL-1β secretion in macrophages requires nonspecific monocyte preactivation in vivo. Then, macrophages trigger NLRP3 inflammasome signaling 117 . The SP drives inflammasome activation in macrophages isolated from convalescent COVID-19 patients, correlating with distinct epigenetic and gene expression signatures 117 . The SP is a PAMP that requires macrophage preactivation for NLRP3 inflammasome formation, and vigorous SP-driven inflammasome activity releases IL-1β in the convalescent macrophages of COVID-19 patients 117 . However, it is not released in macrophages from healthy SARS-CoV-2-naive patients. SARS-CoV-2 infection causes profound and long-lived reprogramming of macrophages. This results in augmented immunogenicity of the SARS-CoV-2 SP, an effective vaccine antigen, which promotes potent adaptive and innate immune signaling 117 . SARS-CoV-2 infection can lead to syncytium formation within cells. The syncytia express ACE2 and SP, which produce approximately four micronuclei per syncytium. Remarkably, these micronuclei are highly expressed during the DNA damage response or during cGAS–STING signaling, which is associated with cellular devastation and poor immune reactions 118 119 . Pathogenic platelet factor 4 (PF4)-dependent syndrome can occur after ChAdOx1 nCoV-19 vaccination 120 . Various side effects caused by the vaccine’s SP appear in a real-time setting. The SP has a unique pathological mechanism: there are strange similarities with amyloid disease-associated blood coagulation and fibrinolytic disturbances together with neurologic and cardiac problems. The protease neutrophil elastase (NE) efficiently cleaves SP, exposes amyloidogenic segments, and accumulates the most amyloidogenic synthetic spike peptide, but full-length folded SP does not form amyloid fibrils 121 122 . SARS-CoV-2 SP vaccination establishes long-lived SP–specific plasma cell reservoirs in the bone marrow of nonhuman primates 123 . The SP might have induced immune reactions in humans. Lipid nanoparticles of the formulated nucleoside-modified mRNAs of SPs are stabilized in their prefusion conformation. They induce an immune reaction involving IL-2 + CD8 + and CD4 + T helper type 1 cells or IFNγ+ cells 124 . Lipid nanoparticles encode the prefusion conformation of SP. General adverse reactions include pain, swelling, redness, muscle pain, headache, fever, and chills after vaccination. Adverse events of special interest (AESI) included anaphylaxis, life-threatening disease, permanent disability/sequelae, and death. The overall seroprevalence of Korean anti-SARS-CoV-2 was very low on September 6, 2021, but the incidence of AESI was very high, as was the case in England during the pandemic. We compared AESI after vaccination in England and South Korea (Fig. 6). These findings suggested that AESI might originate from immune reactions induced by lipid nanoparticles, including the SARS-CoV-2 SP, in mRNA vaccines 12 117 123 124 . Like other RNA viruses, SARS-CoV-2 undergoes genetic evolution and develops mutations over time, resulting in the emergence of multiple variants that may have different characteristics than their ancestral strains 125 126 . The wild-type/Wuhan variant S1 is highly proinflammatory in zebrafish, but the SP of the SARS-CoV-2 variants of interest shows differential proinflammatory effects 127 . Moreover, the SP signals through TLR2 and activates NLRP3 in human macrophages from convalescent patients with COVID-19 but not from healthy SARS-CoV-2–naïve individuals 117 . SP can prime the NLRP3 inflammasome and enhance caspase-1 activity through NF-κB signaling. S1 interacts with amyloid-beta, prion protein, α-Syn, and tau, presumably through heparin-binding domains, to form homopolymers or heteropolymers resembling amyloid fibrils in the neurodegenerative process of misfolded protein disorders in the brain and increases the protein level of p38 MAPK in BV-2 microglia. S1 also binds to transactive response DNA-binding protein 43 (TDP-43) and RNA-binding motifs (RRMs); TDP-43 RRM is involved in amyotrophic lateral sclerosis (ALS) and AD. The interaction of the SP with the prion protein is more robust than that with amyloid-beta, tau, or α-Syn 28 98 128 . The hyperinflammatory state of COVID-19 triggers CNS neuroinflammation by activating astrocytes and microglia. This condition could facilitate prion-like pathology 129 . Like other prion proteins, the SP contains several prionogenic domains. SP triggers a neurodegenerative condition known as prion-disease-like pathology 130 . SP can catalyze the aggregation of aggregation-prone proteins in the brain, and spike-derived peptides can act as functional amyloids. Cross-reactive antibodies can originate from many reported complications, such as the worsening of demyelinating diseases, Guillain–Barré syndrome, immune thrombotic thrombocytopenia, and stroke 131 . As a result, rare hypersensitivity reactions to mRNA-based SARS-CoV-2 vaccines develop, such as anaphylaxis, chest pain, chills, flushing, hypertension, and tachycardia 12 132 . In addition, two distinct self-limiting syndromes, myocarditis and pericarditis, occur in only one patient after COVID-19 vaccination. Specifically, myocarditis develops rapidly in younger patients. It occurred mainly after the second vaccination. However, pericarditis, which occurs after receiving mRNA vaccines, affects older people after the first or second vaccination 133 . 7. Immunological memory engram pathway A single or double layer of invaginated pia forms an interstitial fluid-filled space in the perivascular space in the brain. The space represents an extension of the extracellular fluid space around the intracranial vessels that descend into the brain parenchyma 134 . Human sensory stimuli and abnormal muscular sensations affect breathing via the cerebral cortex and hypothalamus 135 136 . The substrate of information is stored in cells termed engram cells 137 . The brain can trigger immune reactions in patients with COVID-19. The subsequent reactivation of the engram stimulates memory retrieval of immune-related information in the insular cortex 138 . Chemogenetic reactivation reflects the inflammatory conditions described in the insular cortex 139 . The immunological memory engram pathway can restore the initial disease state during COVID-19 pathogenesis 140 . SARS-CoV-2 infection during the fetal period may alter the normal functioning of the brain region where memory engrams are generated and affect neuronal progenitor cells 141 . The massive infection rate in young people leads to the possibility of an increase in the incidence of congenital infections and originating cognitive alterations in terms of new variants; consequently, neuronal circuit anomalies may indicate vulnerability to mental problems throughout life 141 142 143 (Fig. 7) . SARS-CoV-2 may disrupt BBB dysfunction by damaging the choroid plexus epithelium through cytokine, chemokine, and adhesion molecule storms 144 145 . The neuropathology of COVID-19 brains was significantly greater than the microgliosis and T-cell infiltration in COVID-19-free patients. Altered brain T-cell-microglia interactions are linked to profound neuroinflammation 146 . This might trigger inflammasomes and pyroptosis in the CNS. Brainstem involvement could explain sudden deaths by respiratory failure 147 148 149 . COVID-19 is characterized by the rapid development of acute lung injury, ARDS, death due to dysregulated cytokine release, disseminated intravascular coagulation (DIC), multisystem failure, and pneumonia. However, COVID-19 causes unique type L or H phenotype lung injury and requires different ventilatory approaches, depending on the underlying physiology 54 . Often, preexisting neurological disease may become clinically evident or worsen to immune suppression or modulation 150 . ACE2 expression in the lungs is modest compared to that in other organs, such as the heart, kidneys, and small intestines. However, TLR4 is expressed intracellularly on the whole body's dendritic, epithelial, and endothelial cells 151 152 . Conventional dendritic cells are highly specialized antigen-presenting cells that are key initiators and regulators of T-cell-mediated immunity, and their absence in a murine line lacking conventional dendritic cells results in consequent impaired CD8+ T-cell responses and subsequently in a significant increase in the SARS-CoV-2 viral load in the lungs 153 . Microglia and astrocytes participate in immune-to-brain communication during immune activation. Glia, microglia, and astrocytes propagate inflammatory signals and influence physiological responses in the body 154 . Janus kinase (JAK)1-dependent type 2 cytokines promote atopic dermatitis and asthma, and human JAK1 gain-of function variant ( JAK1 GoF ) leads to the development of spotanous atopic dermatitis and staggering of JAK1 in the vagus nerve to induce lung inflammation. Subsequent genetic expression suppresses group 2 ILC function and allergic airway inflammation. 155 ACE2 is localized to the cytoplasm, and its expression appears to be highly regulated by other renin-angiotensin system components. In transgenic mouse brains, ACE2 is present in the cytoplasm of neuronal cell bodies but not in glial cells. ACE2 in transgenic mice was significantly increased in an area lacking the blood‒brain barrier and sensitive to blood-borne angiotensin II 156 . Activating the peripheral immune system via the immunologically coordinated engram pathway elicits exaggerated COVID-19 symptoms. This immunological memory engram pathway is activated during COVID-19 pathogenesis . 8. Excess acetylcholine pathway activity in dementia patients with anti-Alzheimer’s disease SARS-CoV-2 was shown to trigger neuroinflammation in the olfactory mucosa in AD patients 157 , and an analgesic agent against neuroinflammation was shown to prevent and treat AD exacerbation 158 . 8.1 More details on rationale We observed the effects of excess acetylcholine in combination with the drug Alzheimer’s disease (AD) (AAD) on the sustained viral RNA interferon response. VRDs cause lung inflammation and inflammatory cytokine production. Participants were randomized to VRDs after prescribing dapsone as a standard treatment or AADs as AD symptom treatments from 2005 to 2019 in an RCT. The incidence of endemic diseases on Sorok Island, South Korea, sharply increased from 2008 to 2009; that of chronic obstructive pulmonary disease (COPD) increased rapidly in 2012 and 2013; that of acute bronchitis increased from 2012 to 2014; and that of pneumonia increased in 2013 compared to earlier years. The equation for the use of dapsone in combination with acetylation as a preventive treatment for VRDs and excess ACh in AADs (AA equation) was strongly negatively correlated with the incidence of bronchitis and COPD. Excess ACh produced by AADs exacerbates bronchitis and COPD 159 . The muscarinic (M) and nicotinic ACh receptors play life-threatening roles in regulating immune function. Viral infection and interferon treatment cause the release of IFN-γ, decrease M2 receptor gene expression at parasympathetic nerve endings, and ultimately inhibit M2 receptor gene expression 59 61 . COVID-19 is regarded as a hyperinflammatory disease characterized by cytokine release by harmful immune cells. However, the plasma concentrations of these viruses are close to those provoked by classical viral respiratory infections (VRDs), such as influenza 160 161 . VRDs and IFN-1 induce the loss of inhibitory M2 receptor function and gene expression in cultured airway parasympathetic neurons. Moreover, the excess ACh produced by AADs appears to inhibit the production of the ACh receptor, which prevents virus invasion 159 (Fig. 8) . The cohort study indicated another exacerbating factor related to the viral diseases on Sorok Island. 8.2 Supporting evidences As of April 17, 2022, there were 55,841 cases of COVID-19 reinfection in South Korea, for an incidence rate of 0.35%. Ninety days after the initial diagnosis, there were 53,301 cases of reinfection, which accounted for 95.5% of the total cases. A total of 99.0% of reinfection cases occurred during the period when the omicorn virus was dominant. There were 72 patients with exacerbated COVID-19; 70 (97.2%) patients had exacerbated disease after 50 years of age, and 52 (100%) patients died after 50 years of age 162 . Sixty-seven of the 72 cases (93.1%) occurred in nursing hospitals and homes. Patients in nursing hospitals and homes take the following AD drugs: donepezil, choline alfoscerate, rivastigmine, galantamine, and memantine 163 . We compared higher risk subjects who had elapsed since receiving the third vaccination because the fourth COVID-19 vaccine dose was first released from February 16 to April 30, 2022. We analyzed the data of 1,509,970 participants in the high-risk groups, namely, residents of patients in elderly care hospitals and facilities (E1) and immunocompromised individuals (E2). Standardizing per 100,000, infection after the third vaccine was 71.7% (E1) and 28.3%, and severity was 89.4% (E1) and 10.6% (E2), death was 92.0% (E1) and 8.0% (E2), and infection after the fourth vaccine was 74.2% (E1) and 25.8% (E2). The severity of infection was 91.5% (E1) and 8.5% (E2), and the mortality rates were 93.8% (E1) and 6.2% (E2) 164 . One major factor is that, compared with E2, E1 has excess ACh, which increases susceptibility to infection and exacerbates severity and mortality. Excess ACh appears to inhibit ACh receptors to promote IFN production during viral invasion 159 165 . Excess ACh related to AD and related dementias is an underlying or contributing cause of excess mortality in nursing homes, long-term care settings, homes, and medical facilities 166 167 . 8.3 Limitations A wide variety of factors simultaneously act as aggravating factors. Increased levels of oxidative stress, desensitized inflammation, and immune responses, and alterations to genes associated with olfaction were shown in the transcriptomic signatures of olfactory mucosa cells at the air-liquid interface from individuals with AD 157 . Gut microbiota imbalances can trigger several immune disorders through the activity of T cells, both near and distant from the site of induction 168 . The gut microbiota drives systemic antiviral immunity via IFN-I priming, and microbiota-driven IFN-I priming involves the cGAS–STING axis 169 . Nevertheless, the nucleotide-binding oligomerization domain containing 2 (NOD2) in the hypothalamus recognizes neuropeptides and fragments of bacterial cell walls, which change temperature regulation and feeding behavior in mice, particularly older female mice 170 . These findings explain the multidimensional roles of human IFN in regulating senescence, autophagy, apoptosis, antitumor effects, and cell metabolism 171 . Discussion Perspective on implications and limitations ILC3s are essential for host defense against infection and tissue homeostasis. ILC3s depend on the transcription factor retinoic acid-related orphan receptor-gamma γt (RORγt). It plays a role in angiogenesis, initiating ectopic pulmonary lymphoid aggregates 48 . In addition, ILC3s harboring NRP1 (NRP1 + ILC3s) are found in ectopic lymphoid aggregates in patients with chronic lung disease. NRP1 + ILC3s also potentially contribute to inflammation and vascularization 46 . NRP1 + ILC3s are present in the lymphoid tissues and lung tissues of smokers and COPD patients. NRP1 + ILC3s produce more cytokines than ILC3s without NRP1 (NRP1 - ILC3s) 48 . The gut microbiota with acetate modulates ILC3 immunity 172 . The gut microbiota drives systemic antiviral immunity. T and B cells in the mucosa play pivotal roles in maintaining immune homeostasis by suppressing responses to harmless antigens and ensuring the integrity of the barrier functions of the gut mucosa 168 . The microbiota mediates systemic IFN-I priming via DNA-containing membrane vesicles 169 . The prevention of microbiota-driven IFN-I involves the cDNA sensor cGAS–STING axis 169 .The microbiota influences position-specific phenotypes and functions 171 . Moreover, ACh excess by AADs might inhibit ACh receptors for IFN production and exacerbate COVID-19 159 162 164 . COVID-19 induces an immune response in CD8+ T cells, in which feedback activates the NLRP3 inflammasome in an antigen-dependent manner to promote IL-1β maturation on APCs 173 174 175 . CD8+ T cells might originate from T-cell activation caused by HLA polymorphisms 176 . T cells from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQ13:01KLIANQF 177 . At least 20% of individuals with an HLA-B*15:01 status are asymptomatic 178 179 . The weak binding affinity of HLA polymorphisms might contribute to SARS-CoV-2 Omicron’s immune evasion 180 . In viral diseases, excessive production or decreased production of IFN may be an important factor in ultimately worsening pathology. However, in the eight studies in this study, too many complex and diverse pathways are involved in IFN, making it difficult to find treatments that can effectively and efficiently manage it. An outlook on important questions remaining and directions for future investigations Activating cytokines or PAMPs leads to the transcriptional upregulation of canonical and noncanonical inflammasome components 181 . IFN-I-activated microglia and other brain cells arise and expand in amyloidosis, and IFN-I signaling promotes plaque accumulation in neural cells 182 . Manry et al. reported that circulating autoantibodies neutralizing IFN-α, IFN-ω, and IFN-β increased fatality in 1,261 patients who died and 34,159 individuals from the general population 183 . Among the COVID-19-positive veterans who were in the Armed Forces, a previous aspirin prescription was clinically significantly associated with a decrease in overall mortality at 14 days (OR, 0.38) and 30 days (OR, 0.38) 184 . Sera from patients with COVID-19 have elevated levels of cell-free DNA, myeloperoxidase (MPO)-DNA complexes, and citrullinated histone H3. The levels of cell-free DNA and MPO-DNA were high in hospitalized patients receiving mechanical ventilation or breathing room air 185 . Dexamethasone administered at a cumulative dose between 60 and 150 mg was associated with reduced mortality only in patients requiring respiratory support 186 . In COVID-19 and other ARDS cases, a high neutrophil-to-lymphocyte ratio (NLR) is associated with increased myeloid-derived suppressor cells (MDSCs) 187 188 . An elevated NLR and typical bone marrow emergency granulopoiesis in COVID-19 patients are related to increased MDSC numbers 189 190 . MDSCs increase immunosuppressive activity and are critical during severe COVID-19 191 . According to an RCT, the incidence of VRDs associated with dapsone was lower than that associated with VRDs without dapsone 159 . Dapsone treatment was associated with a lower NLR in the ICU 57 158 192 193 . The HLA polymorphisms might be associated with Omicron evasion 180 and dapsone hypersensitivity is susceptible to the expression of HLA-B*13:01 194 195 . It relates the treatment asymptomatic with an HLA-B*15:01 status 178 179 . Anticatalysis might be used as an asymptomatic treatment for COVID-19, as in asymptomatic individuals carrying HLA-B*15:01. We explored immune strategies for preventing COVID-19-related exacerbation of pathophysiology ( Table 2) . Conclusion COVID-19 is exacerbated via seven pathways. COVID-19 is exacerbated by ACE2-TLR4, NRP1, SAMHD1, inflammasome, cGAS–STING, SP, and immunologic engram. Moreover, excess ACh during SARS-CoV-2 variant invasion might inhibit ACh receptors to promote IFN production, but the excess ACh pathway requires further validation. The first-line anti-catalytic triad needs to prevent and block pathological processes, mutations, and deterioration. Methods The National Agency approved this study for the Management of Life-sustaining Treatment, which certified that life-sustaining treatments were managed properly (Korea National Institute for Bioethics Policy (KoNIBP) approval number P01-202007-22-006). In 2021, as external activities were difficult during the pandemic era, we analyzed SCI journals according to L. Wittgenstein's Tractatus Logico-Philosophicus 196 . We investigated and pictured the SARS-CoV-2 penetration route with seven deductions. When these are called basic propositions, the proposition must be the truth function of the basic proposition. If If it is a tautology of (p, q) (T T T T), then p is p (p ⸧ p) and q is q (q ⸧ q). An easy way to prove these is to observe whether the experimental results found are repeated over a period of 1-2 years. Inclusion criteria. Through information search, key words were connected based on the research results. The order is as follows: 1) the angiotensin-converting enzyme 2 (ACE2) and Toll-like receptor (TLR), 2) the neuropilin (NRP), 3) the sterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein 1 (SAMHD1) tetramerization, 4) the inflammasome activation, 5) the cytosolic DNA sensor cyclic-AMP synthase (cGAS)/stimulator of interferon genes (STING) (cGAS–STING) signaling, 6) the spike protein with vaccines, and 7) the immunological memory engram. Exclusion criteria: If experimental data was not repeated SCI journals, those were excluded. We published a preprint (related material) on January 14, 2022. Preprint: Lee, J. (2022, January 14). Pathology and Anticatalysis treatment of exacerbated COVID-19. https://doi.org/10.31219/osf.io/t9wjz (version 1. 01/14/2022 09:27:40) (Supplement 2) The preprint was exposed to Views: 617/Downloads: 274. This preprint has been updated to the final version 18 (September 30, 2023) for the support of related information. This study is not a simple retrieval of systemic reviews but rather a prediction of seven pathways using picture theory for the real world during the pandemic 196 . We analyzed the final results on December 3, 2023. In addition, we conducted the data analysis to find new paths. According to the Korea Drug Code of Medicine, the ADs for symptomatic relief are donepezil hydrochloride, rivastigmine, galantamine, and memantine. The ADs used for psychological symptoms were haloperidol, risperidone, quetiapine, olanzapine, aripiprazole, oxcarbazepine, fluvoxamine, escitalopram, trazodone, sertraline, escitalopram, and fluoxetine. The cumulative number of confirmed cases of coronavirus disease 2019 (COVID-19) was 16,130,920 from January 2020 to April 16, 2022. Based on the status of confirmed cases up to April 16, 2022, in the COVID-19 information management system of the Korea Centers for Disease Control and Prevention, a survey of total cases of COVID-19 reinfection was conducted 162 164 . Per the Information Disclosure Act, we obtained relevant information of registration number 9318128 from the Korea Disease Control and Prevention Agency (Supplement 3). A reinfection was defined as a case in which a positive polymerase chain reaction (PCR) or professional rapid antigen test (RAT) result was confirmed 45 days after the first confirmation, regardless of the presence or absence of symptoms. Declarations Ethical Approval The National Agency approved this study for the Management of Life-sustaining Treatment, which certified that life-sustaining treatments were managed properly (Korea National Institute for Bioethics Policy (KoNIBP) approval number P01-202007-22-006). Consent to participate Informed consent was obtained from all individual participants included in the study. Consent to publish The authors affirm that the human research participants provided informed consent for the publication of the manuscript results. Competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Authors' contributions All the authors listed have made substantial, direct, and intellectual contributions to the work and approved it for publication. J.L. designed this study and the methodology and wrote this manuscript; S.C. and K.L. introduced dexamethasone use at O2 2L/min states and proved its safety and effectiveness; C.S., E.L.A. and M.D.C. reviewed the manuscript; M.D.C. examined dexamethasone use. Funding No funding Availability of data and materials No data associated with the manuscript Abbreviations A549 cell A549 cells are adenocarcinomic human alveolar basal epithelial cells, and constitute a cell line. ACE Angiotensin-converting enzyme AD Alzheimer’s disease AESI Adverse events of special interest AIDS Acquired Immune Deficiency Syndrome AGS Aicardi–Goutières syndrome AIM2 Absent in melanoma 2 ALI Air–liquid interface ALP Alkaline phosphatase α-Syn α-synuclein AMI Acute myocardial infarction AMI I/R injury AMI ischemia–reperfusion injury AMPA α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid APC Antigen-presenting cells ARDS Acute respiratory distress syndrome ASC Apoptosis-associated speck-like protein containing a CARD ATF4 Activated parkin via protein kinase RNA-like endoplasmic reticulum kinase-activating transcription factor 4 BBB Blood‒brain barrier BDNF Brain-derived neurotrophic factor BiPAP Bilevel positive airway pressure BV-2 A type of microglial cell derived from C57/BL6 mice CAPS Cryopyrin-associated periodic syndromes CARD Caspase activation and recruitment domain CCNE2 Essential for the control of the cell cycle at the late G1 and early S phases; belongs to the cyclin family CCR5 C–C motif chemokine receptor 5 CH Clonal hematopoiesis, hematopoietic stem and progenitor cells CDK1 Cyclin-dependent kinase 1 CI Confidence interval CK-MB Creatine kinase-MB fraction COPD Chronic obstructive pulmonary disease COX-1 Cyclooxygenase 1 CRP C-reactive protein CRS Cytokine release syndrome CtIP C-terminal binding protein 1 (CtBP1) interacting protein Cyclin-A2 A protein that in humans is encoded by the CCNA2 gene. It is one of the two types of cyclin A: cyclin A1 is expressed during meiosis and embryogenesis while cyclin A2 is expressed in the mitotic division of somatic cells.[ Cyclin D1 A protein required for progression through the G1 phase of the cell cycle Cyclin D3 A cofactor of retinoic acid receptors, modulating their activity in the presence of cellular retinoic acid-binding protein II Cyclin E2 Cyclin E2 is a protein that in humans is encoded by the CCNE2 gene Cyclin-G1 A protein that in humans is encoded by the CCNG1 gene CXCR-4 C-X-C chemokine receptor type 4 DDS 4,4′-Diaminodiphenyl sulfone (dapsone) DPP4 Dipeptidyl peptidase-4 DIC Disseminated intravascular coagulation ECG Electrocardiogram ER Endoplasmic reticulum cGAMP 2′,3′-cyclic GMP-AMT cGAS–STING cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) G6PDH Glucose-6-phosphate dehydrogenase HAART Highly active antiretroviral therapy HIV Human Immunodeficiency Virus HLA Human leukocyte antigen HLA-DRB1 Major histocompatibility complex, class II, DR beta 1 HSPC ICU hematopoietic stem/progenitor cell Intensive care unit IFN Interferon IFNAR2 Interferon-alpha and beta receptor subunit 2 IL Interleukin IL-1β Interleukin-1 beta IMV intensive mechanical ventilation IRF3 Interferon regulatory factor 3 JNK Jun N-terminal kinases LDH Lactate dehydrogenase LDL Low-density lipoprotein LL Lepromatous leprosy LPS Lipopolysaccharide LTP Long-term potentiation M receptor Muscarinic receptor MADDS Monoacetyldapsone MAPK Mitogen-activated protein kinase MCI Mild cognitive impairment MDIG Mineral dust-induced gene MHC Major histocompatibility complex MIS-C/A Multisystem inflammation syndrome in children and adults MPO Myeloperoxidase N receptor Nicotinic receptor NOD2 Nucleotide-binding oligomerization domain containing 2 N protein Nucleocapsid protein MDA5 melanoma differentiation-associated gene 5 mRNA Messenger RNA mtDNA Mitochondrial DNA NACHT Domain conserved in NAIP, CIITA, HET-E, and TP1 NFL Neurofilament light chain NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells NLRC4 NLR Family CARD Domain Containing 4 NLRP3 NOD-, LRR-, and pyrin domain-containing protein 3 NLR family pyrin domain-containing 3 NRP Neuropilin PAI-1 Plasminogen activator inhibitor-1 PAMPs Pathogen-associated molecular patterns PBMCs Human peripheral blood mononuclear cells PD Parkinson’s disease PEDF Pigment epithelium-derived factor PEDFR/iPLA2 PEDF/calcium-independent phospholipase A2 Phosphomimetics Amino acid substitutions that mimic a phosphorylated protein. Phospho-p65 Anti-phospho-NFkB p65 (Ser536) monoclonal antibody (T.849.2) Phospho-IκBα Phospho-IκBα (Ser32/36) (5A5) mouse mAb #9246 PRMT5 Protein arginine methyltransferase 5 PTGS2 Prostaglandin synthase 2 PTM Multiple posttranslational modification RIG-I Retinoic acid-inducible gene I ROS Reactive oxygen species SP Spike glycoprotein of SARS-CoV-2 S1 SARS-CoV-2 spike protein subunit 1 SAMHD1 Sterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein SCLS Systemic capillary leak syndrome RCT Randomized controlled trial SOD Superoxide dismutase TGFβ Transforming growth factor-beta THP-1 A spontaneously immortalized monocyte-like cell line TNF Tumor necrosis factor TLR Toll-like receptor TMPRSS2 Transmembrane protease serine subtype 2 TRIF TLR3-TIR-domain-containing adapter-inducing interferon-β TTS Thrombosis with thrombocytopenia syndrome TREX1 Tthree-prime repair exonuclease 1 TYK2 Tyrosine kinase 2 UCB Umbilical cord blood VRD Viral respiratory disease VSEL Very small embryonic-like stem cell Tables Table 1 COVID-19 picture on the basis of the real world The 1st version 2022-01-14 The last in 2024-01-04 *1 Original Preprint *2 Matched 2020-2021 2022-2024 1. ACE2 and TLRs pathways (25) (Vaduganathan et al, 2020 *3 ) (26) (Kucia et al, 2021) (27,28) (Choudhury & Mukherjee, 2020) (29) (Olajide et al, 2021) (30) (Rannikko et al, 2015) *4 (31) (Conte, 2021) (32) (Jurgens et al, 2012) (33) (Tanaka et al, 2018) (34) (Sparkman et al, 2019) (35) (Muscat & Barrientos, 2021) (36) (Boldrini et al, 2021) (37,38) (Zeberg & Pääbo, 2020) 197 (Vaduganathan et al, 2020) *5 18 (Kucia et al, 2021) *6 20 (Choudhury & Mukherjee, 2020) 28 (Olajide et al, 2021) 29 (Rannikko et al, 2015) 30 (Conte, 2021) 198 (Jurgens et al, 2012) 199 (Tanaka et al, 2018) 200 (Sparkman et al, 2019) 201 (Muscat & Barrientos, 2021) 202 (Boldrini et al, 2021) 31 (Zeberg & Pääbo, 2020) 11 (Devaux et al, 2020) 13 (Kumar et al, 2021) 15 (Chlamydas et al, 2021) 16 (Ratajczak et al , 2021) 17 (Lei et al, 2021) 18 (Kucia et al. 2021) 20 (Choudhury and Mukherjee 2020) 21 (Choudhury et al. 2021) 22 (Patra et al, 2021) 25 (Zhao et al, 2021) 28 (Olajide et al, 2021) 30 (Conte, 2021) 31 (Zeberg & Pääbo, 2020) 12 (Lee, 2023) *7 14 (Shirvaliloo, 2022) 19 (Kronstein-Wiedemann et al. 2022) 24 (Gonzalez et al, 2023) 26 (Manik & Singh, 2022) 27 (Frank et al, 2022) 2. Neuropilin‑1 Pathway (39,40) (Cantuti-Castelvetri et al, 2020; Daly et al, 2020) (41) (Kyrou et al, 2021) (42) (Khan et al, 2021) (43) (Davies et al, 2020) (44) (Zhang et al, 2021) (45) (Zeberg & Pääbo, 2020) *8 (46) (Zeberg & Pääbo, 2021) 32,33 (Cantuti-Castelvetri et al, 2020; Daly et al, 2020) 36 (Kyrou et al, 2021 ) 50 (Khan et al, 2021) 49 (Davies et al, 2020) 42 (Zhang et al, 2021) 41 (Zeberg & Pääbo, 2021) 32 (Daly et al. 2020) 33 (Cantuti-Castelvetri et al. 2020) 34 (Hoffmann et al. 2020) 35 (Mollica, Rizzo, and Massari 2020) 36 (Kyrou et al. 2021) 49 (Davies et al. 2020) 50 (Khan et al. 2021) 51 (Yong 2021) 38 (Group 2020) 39 (Li et al. 2020) 41 (Zeberg and Pääbo 2021) 42 (Zhang, Wadgaonkar, et al. 2021) 44 (Clottu et al, 2021) 46 (Meininger et al, 2020) 54 (Marini & Gattinoni, 2020) 57 (Kanwar et al, 2021) 58 (Ferren et al , 2021) 53 (Lee et al. 2022) 52 (Lucchese et al. 2022) 40 (Kerner and Quintana-Murci 2022) 43 (Zhang et al, 2022) 45 (Spits & Mjösberg, 2022) 55 (Kawano et al, 2023) 56 (Dangarembizi & Drummond, 2023) 3. SAMHD1 tetramerization pathway (54) (Coquel et al, 2018) (55) (White et al, 2013) (56) (Tang et al, 2015) (57) (Franzolin et al, 2015) (58) (Ji et al, 2013) (59) (Yu et al, 2021) (60) (Khan & Sergi, 2020) (61) (Maelfait et al, 2016) (62) (Crow & Manel, 2015) (63) (Rice et al, 2009) 62 (Coquel et al, 2018) 70 (White et al, 2013) 73 (Tang et al, 2015) 203 (Franzolin et al, 2015) 74 (Ji et al, 2013) 75 (Yu et al, 2021) 80 (Khan & Sergi, 2020) 77 (Maelfait et al, 2016) 79 (Crow & Manel, 2015) 78 (Rice et al, 2009) 64 (Bowen et al , 2021) 66 (Cingöz et al, 2021) 75 (Yu et al. 2021) 80 (Khan and Sergi 2020) 81 (Kwan et al , 2021) 71 (Yan, Tang, and Zheng 2022) 72 (Gupta and Mlcochova 2022) 65 (Oo et al. 2022) 67 (Lee et al, 2023) 69 (Fink et al, 2022) 71 (Yan et al, 2022) 72 (Gupta & Mlcochova, 2022) 4. Inflammasome activation pathway (47) (Rodrigues et al, 2020) (48) (Ferreira et al, 2021) (49) (Pan et al, 2021) (50) (Theobald et al, 2021) (51) (Vora et al, 2021) (52) (Ichinohe et al, 2013) (53) (Park et al, 2013) 85 (Rodrigues et al, 2020) 86 (Ferreira et al, 2021) 84 (Pan et al, 2021) 117 (Theobald et al , 2021) *9 204 (Vora et al, 2021) 89 (Ichinohe et al, 2013) 99 (Park et al, 2013) 85 (Rodrigues et al. 2020) 86 (Ferreira et al. 2021) 84 (Pan et al. 2021) 91 (Han et al. 2021) 92 (Rui et al. 2021) 95 (Lee et al, 2020) 96 (Lee et al, 2021) 87 (Rodrigues and Zamboni 2023) 90 (Han et al. 2022) 93 (Deng et al. 2023) 97 (Beckman et al, 2022) 98 (Albornoz et al, 2022) 88 (Wang et al, 2023) 5. cGAS–STING signaling pathway (65) (de Oliveira Mann & Hopfner, 2021) (66) (Paul et al, 2021) (67) (Fengjuan Li, 2021) (68) (Ren et al, 2021) (69) (Gaidt et al, 2017) (70) (Aarreberg et al, 2019) (71) (Bolton et al, 2021) (72) (Hammond & Loghavi, 2021) 104 (de Oliveira Mann & Hopfner, 2021) 109 (Paul et al, 2021) 110 (Fengjuan Li, 2021) 119 (Ren et al , 2021) 94 (Gaidt et al, 2017) 205 (Aarreberg et al, 2019) 206 (Bolton et al, 2021) 207 (Hammond & Loghavi, 2021) 101 (Humphries et al. 2021) 102 (Yum et al, 2021) 103 (Cui et al. 2020) 104 (de Oliveira Mann and Hopfner 2021) 109 (Paul et al, 2021) 110 (Fengjuan Li 2021) 100 (Domizio et al, 2022) 105 (Neufeldt et al. 2022) 108 (Su et al. 2023) 106 (Liu et al, 2022) 107 (Chen & Xu, 2023) 6. Spike protein pathway (73,74) (Bahl et al, 2017; Pardi et al, 2015) (75) (Sahin et al, 2021) (76) (Cho et al, 2021) (77) (Eisfeld et al, 2021) (78) (Diaz et al, 2021) (79) (Ratajczak et al, 2021) (80) (Scully et al, 2021) (81) (Reuters, 2021) (82) (Idrees & Kumar, 2021) (83) (Young et al, 2020) (84) (Chakrabarti et al, 2021) (85) (Schultz et al, 2021) (86) (Vojdani et al, 2021) (87) (Stillman, 2013) (88) (Bowen et al, 2021) (89) (Bowen et al) (90) (Kwan et al, 2021) 208,209 (Bahl et al, 2017; Pardi et al, 2015) 210 (Sahin et al, 2021 211 (Cho et al, 2021) 112 (Eisfeld et al, 2021) 133 (Diaz et al, 2021) 16 (Ratajczak et al , 2021) 120 (Scully et al, 2021) 212 (Reuters, 2021) 128 (Idrees & Kumar, 2021) 129 (Young et al, 2020) 130 (Chakrabarti et al, 2021 131 (Schultz et al, 2021) 213 (Vojdani et al, 2021) 63 (Stillman, 2013) 64 (Bowen et al , 2021) 81 (Kwan et al , 2021) 111 (Örd, Faustova, and Loog 2020) 112 (Eisfeld et al. 2021) 113 (Sergi & Chiu, 2021) 116 (Shirato and Kizaki 2021) 117 (Theobald et al . 2021) 119 (Ren et al . 2021) 120 (Scully et al. 2021) 121 (Cai et al. 2020) 124 (Sahin et al. 2021) 125 (Tao et al, 2021) 128 (Idrees & Kumar, 2021) 129 (Young et al, 2020) 130 (Chakrabarti et al, 2021) 131 (Schultz et al, 2021) 133 (Diaz et al. 2021) 114 (Montezano et al. 2023) 118 (Liu et al. 2022) 122 (Nyström and Hammarström 2022) 123 (Prabhakaran et al, 2024) 12 6 (Lee, 2023) 126 (Yao et al, 2022) 127 (Tyrkalska et al, 2022) 132 (Szebeni et al, 2022) 7. Immunological memory engram pathway (91) (Song et al, 2021) (92) (Schwabenland et al, 2021) (93) (Sepehrinezhad et al, 2021) (94,95) (Lee et al, 2020; Yachou et al, 2020) (96) (Josselyn & Tonegawa, 2020) (97) (Koren et al, 2021) (98) (Gogolla, 2021) (99) (Koike et al, 2021) (100) (Marini & Gattinoni, 2020) (101) (Finsterer & Scorza, 2021) (102) (Fu et al, 2020) (103) (Ferren et al, 2021) (104) (Norden et al, 2016) 214 (Song et al, 2021) 146 (Schwabenland et al, 2021) 147 (Sepehrinezhad et al, 2021) 148,149 (Lee et al, 2020; Yachou et al, 2020) 138 (Josselyn & Tonegawa, 2020) 139 (Koren et al, 2021) 140 (Gogolla, 2021) 215 (Koike et al, 2021) 54 (Marini & Gattinoni, 2020) 150 (Finsterer & Scorza, 2021) 152 (Fu et al, 2020) 58 (Ferren et al , 2021) 154 (Norden et al, 2016) 134 (Troili et al. 2020) 135 (Baig 2020) 136 (Dhont et al. 2020) 138 (Josselyn and Tonegawa 2020) 139 (Koren et al. 2021) 140 (Gogolla 2021) 144 (Zhang, Zhou, et al. 2021) 146 (Schwabenland et al. 2021) 147 (Sepehrinezhad, Gorji, and Sahab Negah 2021) 148 (Lee et al. 2020) 149 (Yachou et al. 2020) 150 (Finsterer and Scorza 2021) 152 (Fu et al. 2020) 137 (Ortega-de San Luis et al, 2023) 141 (Hernandez-Lopez et al. 2023) 145 (Yang et al. 2022) 153 (Bar-On et al, 2023) 155 (Tamari et al, 2024) 8. Excess acetylcholine pathway 160 (Mudd et al, 2020) 161 (Monneret et al, 2021) 165 (Horkowitz et al, 2020) 169 (Erttmann et al, 2022) 170 (Gabanyi et al, 2022) 171 (Liu et al, 2022) 157 (Shahbaz et al, 2023) 158 (Lee et al, 2022) 159 (Lee et al, 2023) 164 (Shim, 2023) 166 (Axenhus et al, 2022) 167 (Chen et al, 2023) *1: The original Preprint file (Supplement 2): Lee, J. (2022, January 14). Pathology and Anticatalysis treatment of exacerbated COVID-19. https://doi.org/10.31219/osf.io/t9wjz *2: Each one was checked and matched with the reference number of this paper. *3: In parentheses, the author and publication year are described to help distinguish the information in the paper. *4: Yellow represents papers published before 2020-2021 at the beginning of the pandemic. *5: The cited paper that used the strikethrough was removed during the 18th update because it did not reflect reality. *6: The papers in bold black indicate the papers used from the beginning to the end. *7: Underlined are papers submitted in 2022-2023. There is also a paper published in 2024. *8: Paper No. 45, 89 in the 1 st version is excluded because it is a preprint. *9: Italics indicate cases where the cited paper has been moved to explain a different mechanism in reality. Table 2 . The Immune Triad for Anticatalysis Treatment Against Exacerbations of COVID-19 Acetylation, cGAS-STING axis Neutrophil, IFN pathways NETs 1 Inflammasome ILCs 4 Cytokine Clinical results Ref. Aspirin IFN active ( * ↓) ILC2s (nasal mucosa↑, blood↓) Mortality (↓) 216 217 Dapsone IFN active (↓) IFN active (↓) MPO-DNA NETs (↓) NLRP3 3 (↓) ILCs (↓) Mortality (↓) NLR ratio (↓) Exacerbation (↓) 12 218 219 220 221 222 223 224 Dexamethasone IFN active (↓) immature neutrophils ( ** ↑) blood ILC2s (↓) Mortality (↓) NLR ratio (↓) 225 226 227 COVID-19 IFN active (↑) IFN active (↑) cell-free DNA, MPO 2 -DNA complexes (↑) NLRP3 (↑) CD8+ T cells (↑) 173 174 1 ) Neutrophil extracellular traps, 2) myeloperoxidase, 3) NLR family pyrin domain-containing 3 (previously known as NACHT, LRR, and PYD domain-containing protein 3 [NALP3] and cryopyrin), 4) innate lymphoid cells, *) decreased, **) increased References 1 Choudhury, A., Mukherjee, G. & Mukherjee, S. 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Immunity 55 , 879-894.e876 (2022). https://doi.org/10.1016/j.immuni.2022.03.018 183 Manry, J. et al. The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies. Proceedings of the National Academy of Sciences 119 , e2200413119 (2022). https://doi.org/doi:10.1073/pnas.2200413119 184 Osborne, T. F. et al. Association of mortality and aspirin prescription for COVID-19 patients at the Veterans Health Administration. PloS one 16 , e0246825 (2021). 185 Panda, R. et al. A functionally distinct neutrophil landscape in severe COVID-19 reveals opportunities for adjunctive therapies. JCI Insight 7 (2022). https://doi.org/10.1172/jci.insight.152291 186 Hoertel, N. et al. Dexamethasone use and mortality in hospitalized patients with coronavirus disease 2019: A multicentre retrospective observational study. British Journal of Clinical Pharmacology 87 , 3766-3775 (2021). https://doi.org/https://doi.org/10.1111/bcp.14784 187 Codd, A. S. et al. Neutrophilia, lymphopenia and myeloid dysfunction: A living review of the quantitative changes to innate and adaptive immune cells which define COVID-19 pathology. Oxford open immunology 2 , iqab016 (2021). 188 Higaki, A. et al. Predictive value of neutrophil-to-lymphocyte ratio for the fatality of COVID-19 patients complicated with cardiovascular diseases and/or risk factors. Scientific reports 12 , 1-9 (2022). 189 Alsalman, A., Al-Mterin, M. A. & Elkord, E. Role of T Regulatory Cells and Myeloid-Derived Suppressor Cells in COVID-19. Journal of Immunology Research 2022 (2022). 190 Perfilyeva, Y. V. et al. Myeloid-derived suppressor cells in COVID-19: A review. Clinical Immunology , 109024 (2022). 191 Schrijver, I. T. et al. COVID‐19 rapidly increases MDSCs and prolongs innate immune dysfunctions. European Journal of Immunology (2022). 192 Kanwar, B. A., Khattak, A., Balentine, J., Lee, J. H. & Kast, R. E. Benefits of Using Dapsone in Patients Hospitalized with COVID-19. 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Influenza infection induces neuroinflammation, alters hippocampal neuron morphology, and impairs cognition in adult mice. Journal of Neuroscience 32 , 3958-3968 (2012). 199 Tanaka, N., Cortese, G. P., Barrientos, R. M., Maier, S. F. & Patterson, S. L. Aging and an immune challenge interact to produce prolonged, but not permanent, reductions in hippocampal L-LTP and mBDNF in a rodent model with features of delirium. Eneuro 5 (2018). 200 Sparkman, N. L., Buchanan, J. B., Dos Santos, N. L., Johnson, R. W. & Burton, M. D. Aging sensitizes male mice to cognitive dysfunction induced by central HIV-1 gp120. Experimental gerontology 126 , 110694 (2019). 201 Muscat, S. M. & Barrientos, R. M. The Perfect Cytokine Storm: How Peripheral Immune Challenges Impact Brain Plasticity & Memory Function in Aging. Brain Plasticity 7 , 47-60 (2021). https://doi.org/10.3233/BPL-210127 202 Boldrini, M., Canoll, P. D. & Klein, R. S. How COVID-19 Affects the Brain. JAMA Psychiatry 203 Franzolin, E., Salata, C., Bianchi, V. & Rampazzo, C. The Deoxynucleoside Triphosphate Triphosphohydrolase Activity of SAMHD1 Protein Contributes to the Mitochondrial DNA Depletion Associated with Genetic Deficiency of Deoxyguanosine Kinase *. Journal of Biological Chemistry 290 , 25986-25996 (2015). https://doi.org/10.1074/jbc.M115.675082 204 Vora, S. M., Lieberman, J. & Wu, H. Inflammasome activation at the crux of severe COVID-19. Nature Reviews Immunology 21 , 694-703 (2021). https://doi.org/10.1038/s41577-021-00588-x 205 Aarreberg, L. D. et al. Interleukin-1β Induces mtDNA Release to Activate Innate Immune Signaling via cGAS-STING. Molecular Cell 74 , 801-815.e806 (2019). https://doi.org/https://doi.org/10.1016/j.molcel.2019.02.038 206 Bolton, K. L. et al. Clonal hematopoiesis is associated with risk of severe Covid-19. Nature Communications 12 , 5975 (2021). https://doi.org/10.1038/s41467-021-26138-6 207 Hammond, D. & Loghavi, S. Clonal haematopoiesis of emerging significance. Pathology 53 , 300-311 (2021). https://doi.org/https://doi.org/10.1016/j.pathol.2021.02.005 208 Pardi, N. et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. Journal of Controlled Release 217 , 345-351 (2015). 209 Bahl, K. et al. Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Molecular Therapy 25 , 1316-1327 (2017). 210 Sahin, U. et al. BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans. Nature , 1-6 (2021). 211 Cho, A. et al. Anti-SARS-CoV-2 receptor-binding domain antibody evolution after mRNA vaccination. Nature (2021). https://doi.org/10.1038/s41586-021-04060-7 212 Reuters. in Reuters (2021 Guardian News & Media Limited or its affiliated companies, The Guardian, Kings Place, 90 York Way, London, N1 9GU, United Kingdom., 2021). 213 Vojdani, A., Vojdani, E. & Kharrazian, D. Reaction of human monoclonal antibodies to SARS-CoV-2 proteins with tissue antigens: Implications for autoimmune diseases. Frontiers in Immunology 11 , 3679 (2021). 214 Song, E. et al. Neuroinvasion of SARS-CoV-2 in human and mouse brain. J. Exp. Med. 218 , e20202135 (2021). https://doi.org/10.1084/jem.20202135 215 Koike, K. et al. Danger perception and stress response through an olfactory sensor for the bacterial metabolite hydrogen sulfide. Neuron 109 , 2469-2484.e2467 (2021). https://doi.org/10.1016/j.neuron.2021.05.032 216 Dai, J. et al. Acetylation Blocks cGAS Activity and Inhibits Self-DNA-Induced Autoimmunity. Cell 176 , 1447-1460.e1414 (2019). https://doi.org/10.1016/j.cell.2019.01.016 217 Eastman, J. J. et al. Group 2 innate lymphoid cells are recruited to the nasal mucosa in patients with aspirin-exacerbated respiratory disease. Journal of Allergy and Clinical Immunology 140 , 101-108.e103 (2017). https://doi.org/https://doi.org/10.1016/j.jaci.2016.11.023 218 Lee, J.-h., An, H. K., Sohn, M.-G., Kivela, P. & Oh, S. 4,4′-Diaminodiphenyl Sulfone (DDS) as an Inflammasome Competitor. International Journal of Molecular Sciences 21 , 5953 (2020). 219 Chakraborty, A., Panda, A. K., Ghosh, R. & Biswas, A. DNA minor groove binding of a well known anti-mycobacterial drug dapsone: a spectroscopic, viscometric and molecular docking study. Arch. Biochem. Biophys. 665 , 107-113 (2019). https://doi.org/10.1016/j.abb.2019.03.001 220 Cho, S. C. et al. Protective effect of 4,4'-diaminodiphenylsulfone against paraquat-induced mouse lung injury. Exp Mol Med 43 , 525-537 (2011). https://doi.org/10.3858/emm.2011.43.9.060 221 Mahale, A. et al. Dapsone prolong delayed excitotoxic neuronal cell death by interacting with proapoptotic/survival signaling proteins. J Stroke Cerebrovasc Dis 29 , 104848 (2020). https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.104848 222 Rashidian, A. et al. Dapsone reduced acetic acid-induced inflammatory response in rat colon tissue through inhibition of NF-kB signaling pathway. Immunopharmacol Immunotoxicol 41 , 607-613 (2019). https://doi.org/10.1080/08923973.2019.1678635 223 Mohammad Jafari, R. et al. Dapsone Ameliorates Colitis through TLR4/NF-kB Pathway in TNBS Induced Colitis Model in Rat. Archives of Medical Research 52 , 595-602 (2021). https://doi.org/https://doi.org/10.1016/j.arcmed.2021.03.005 224 Yousefi-Manesh, H. et al. Protective effect of dapsone against bleomycin-induced lung fibrosis in rat. Experimental and Molecular Pathology 124 , 104737 (2022). https://doi.org/https://doi.org/10.1016/j.yexmp.2021.104737 225 Claman, H. N. Corticosteroids and lymphoid cells. New England Journal of Medicine 287 , 388-397 (1972). 226 Nagakumar, P. et al. Pulmonary type-2 innate lymphoid cells in paediatric severe asthma: phenotype and response to steroids. European Respiratory Journal 54 , 1801809 (2019). https://doi.org/10.1183/13993003.01809-2018 227 Liu, S. et al. Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: The role of thymic stromal lymphopoietin. Journal of Allergy and Clinical Immunology 141 , 257-268.e256 (2018). https://doi.org/10.1016/j.jaci.2017.03.032 Additional Declarations The authors declare no competing interests. Supplementary Files Supplement1.docx Supplement fig. 1 from reference. Supplement2COVID1920220114T002739.406Z.pdf The first preprint. 2022.01.14. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3849399","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":266667252,"identity":"ca6730fc-146f-4c84-a67e-e31254d2a052","order_by":0,"name":"Jong hoon Lee","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYFACxgYQKQfjJiDECGgxJkULBCTCFBHWIt9+uPFxQY1N+vb29ocPfu6xy2OQPnyAceYe3FoMziQ2G884lpY758wZY8OeZ8nFDHxpCYwbnuHRIsHYJs3bcDh3hkQOmwTPgQOJDTw8BowPDuBx2AzG9t+8Df/TJeSfP//5B6yF/wNeLQw3GNuYeRsOJEhIMJgxQ21hYNyARwvIL9I8x5INZ/DkGEvLHEhObONhMzg4A5/D2o8//MxTYycvwX784cc3B+wS+3mYHz7swecwDMAGxCRpGAWjYBSMglGACQAt2VFShmRu5wAAAABJRU5ErkJggg==","orcid":"","institution":"Seoul National University College of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jong","middleName":"hoon","lastName":"Lee","suffix":""},{"id":266667253,"identity":"203c3dcd-d8af-4922-a31d-b0081e5f13df","order_by":1,"name":"Consolato Sergi","email":"","orcid":"","institution":"University of Ottawa","correspondingAuthor":false,"prefix":"","firstName":"Consolato","middleName":"","lastName":"Sergi","suffix":""},{"id":266667254,"identity":"15ac5c51-2f90-4482-b72c-d11140c0b640","order_by":2,"name":"Richard E. Kast","email":"","orcid":"","institution":"IIAIGC Study Center","correspondingAuthor":false,"prefix":"","firstName":"Richard","middleName":"E.","lastName":"Kast","suffix":""},{"id":266667255,"identity":"b571b98d-5883-4346-b3ff-bd30587d0f56","order_by":3,"name":"Badar A. Kanwar","email":"","orcid":"","institution":"Haider Associates","correspondingAuthor":false,"prefix":"","firstName":"Badar","middleName":"A.","lastName":"Kanwar","suffix":""},{"id":266667256,"identity":"39cf1e48-0754-4f08-bc88-6c3d3d4dc16d","order_by":4,"name":"Eric L. Altschuler","email":"","orcid":"","institution":"Metropolitan Hospital New York","correspondingAuthor":false,"prefix":"","firstName":"Eric","middleName":"L.","lastName":"Altschuler","suffix":""},{"id":266667257,"identity":"918cc8a7-9cc1-4f21-9423-a8311e21dc74","order_by":5,"name":"Jean Bourbeau","email":"","orcid":"","institution":"McGill University Health Centre","correspondingAuthor":false,"prefix":"","firstName":"Jean","middleName":"","lastName":"Bourbeau","suffix":""},{"id":266667258,"identity":"8eddd091-94b7-47c1-95a8-ffc44002e3fb","order_by":6,"name":"Sangsuk Oh","email":"","orcid":"","institution":"Ewha Womans University","correspondingAuthor":false,"prefix":"","firstName":"Sangsuk","middleName":"","lastName":"Oh","suffix":""},{"id":266667259,"identity":"685a92ed-b361-4fd2-b044-1a5d4adfad71","order_by":7,"name":"Mun-Gi Sohn","email":"","orcid":"","institution":"KyungHee University College of Life Science","correspondingAuthor":false,"prefix":"","firstName":"Mun-Gi","middleName":"","lastName":"Sohn","suffix":""},{"id":266667260,"identity":"1afff983-1970-49ca-8ace-b3717b53fcee","order_by":8,"name":"Kun Ho Lee","email":"","orcid":"","institution":"Chosun University","correspondingAuthor":false,"prefix":"","firstName":"Kun","middleName":"Ho","lastName":"Lee","suffix":""},{"id":266667261,"identity":"5abeb632-8122-4f97-bc5b-aa18a0662a17","order_by":9,"name":"Michael D. Coleman","email":"","orcid":"","institution":"Aston University","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"D.","lastName":"Coleman","suffix":""}],"badges":[],"createdAt":"2024-01-10 03:29:11","currentVersionCode":2,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-3849399/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-3849399/v2","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12985-024-02506-8","type":"published","date":"2024-09-27T00:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":54319207,"identity":"e7cd7b4c-637f-4a54-8f09-4da292968921","added_by":"auto","created_at":"2024-04-08 18:48:05","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":4544558,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMechanism of activation of TLR4\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePeripheral immune insults are known to activate the pattern recognition receptor TLR4. TLR4 leads to the activation of nuclear factor-κB (NF-κB). Ultimately, TLR4 produces immature IL-1β, which is cleaved by caspase-1 and inflammasome components into mature IL-1β. As a result, IL-1β is released into the extracellular fluid. IL-1β elicits multiple effects on synaptic plasticity-related processes, including suppression of BDNF (brain-derived neurotrophic factor) production, reduction of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor membrane expression, and inhibition of LTP (long-term potentiation). IL-1β elicits multiple effects on synaptic plasticity-related processes, including suppression of BDNF production, reduction of AMPA receptor membrane expression, and inhibition of LTP. SARS-CoV-2 also activates TLR4, leading to the activation of NF-κB and ultimately the production of immature IL-1β. The transcriptional activation of NF-κB induces and releases proinflammatory cytokines. The final sequence of NF-κB activation is joined with cytokine receptor- and TLR-mediated signaling cascades. SARS-CoV-2 induces TLR4-mediated and endoplasmic reticulum (ER)-induced NF-κB activation. They play a pivotal role in the neurodegenerative process of misfolded protein disorders.\u003c/p\u003e","description":"","filename":"fig1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3849399/v2/9fd84ae373ae07036c8315ea.jpeg"},{"id":54319210,"identity":"4096ba92-f729-4501-a24a-7d7eb7ac804b","added_by":"auto","created_at":"2024-04-08 18:48:05","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":9285934,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociation of neuropilins with SARS-CoV-2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNeuropilins are transmembrane glycoproteins that regulate neurogenesis and angiogenesis by complexing with various receptors and predominantly act as coreceptors because they have a microscopic cytoplasmic domain. Neuropilins thus rely upon other cell surface receptors, such as ACE2, to transduce signals across the cell membrane, mitochondria and nucleus. Neuropilin 1,2 can be found in soluble forms produced by alternative splicing or ectodomain shedding from the cell surface. The neuropilin complex comprises 1) plexin receptors with class 3 semaphorin ligands, 2) vascular endothelial growth factor (VEGF) receptors with VEGF ligand 1 (VEGFR1), and 3) integrin, a receptor with α and β subunits 4, and transforming growth factor beta (TGF-β). SARS-CoV-2 spike glycoprotein subunit 1 binds to ACE2. In contrast, subunit 2 mediates the fusion of the spike protein with cell membranes via transmembrane protease serine 2 (TMPRSS2). Furin cleaves the spike protein at two subunit 1-subunit junctions, which consist of a sequence of essential amino acids. Subunit 1-Subunit two junction cleavage exposes a carboxyl-terminal motif conforming to the C-end rule motif. This C-end rule motif of subunit 1 can bind to neuropilin-1 via its b1 domain [12]. Innate lymphoid cells (ILCs) include non-T and non-B lymphoid cells in humans. ILCs are divided into three groups based on their distinct cytokine profiles and transcription factor profiles. Neuropilin-1 is a tissue-specific marker of lung group 2 innate lymphoid cells (ILC2s). TGFβ1–neuropilin-1 signaling enhances ILC2 function and type 2 immunity, which identifies neuropilin-1 as a tissue-specific regulator of lung-resident ILC2s and features a neuropilin-1 regulator as a potential therapeutic for pulmonary fibrosis.\u003c/p\u003e","description":"","filename":"Fig2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3849399/v2/25c962841cbdd22dce6e0571.jpeg"},{"id":54319572,"identity":"a3e782d4-6e93-4fcd-95d0-21b116e0307d","added_by":"auto","created_at":"2024-04-08 18:56:06","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":4565570,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRespiratory muscles during healthy breathing.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRespiratory muscles cannot be intentionally activated during healthy breathing. Human sensory stimuli and abnormal muscular sensations affect breathing via the cerebral cortex and hypothalamus. ACE2 is localized to the cytoplasm, and its expression can be highly regulated by other RAAS components in the nucleus tractus solitarius/dorsal motor nucleus on the vagus and ventrolateral medulla. SARS-CoV-2 may exhibit tropism because the brainstem has relatively high expression levels of the ACE2 receptor compared with other brain regions. Neuropilin-1 is a coreceptor that facilitates SARS-CoV-2 infection in ACE2 and is expressed in the brainstem. The recognized pathways involve transsynaptic transfer via peripheral, olfactory, or cranial nerves and BBB penetration from the systemic circulation to affect the brainstem. SARS-CoV-2 may exhibit tropism to the brainstem, which has relatively high expression of the ACE2 receptor.\u003c/p\u003e","description":"","filename":"Fig3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3849399/v2/eb283b4488107aad26a1a340.jpeg"},{"id":54319216,"identity":"23673602-5e22-40be-bf5b-ba5aaaa138c0","added_by":"auto","created_at":"2024-04-08 18:48:06","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":2956002,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eActivated cGAS initiates type 1 IFN production at the perinuclear Golgi.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eActivated cGAS catalyzes the conversion of cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) to cytosolic DNA. cGAMP binds to STING and triggers STING–tank-binding kinase 1 (TBK1)–interferon regulatory factor 3 (IRF3) signaling. TBK1 kinase phosphorylates IRF3, and phosphorylated IRF3 enters the nucleus. At that point, NF-κB triggers the expression of IFN-1 and proinflammatory cytokine genes.\u003c/p\u003e","description":"","filename":"Fig4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3849399/v2/e6a62b7f32029d9a978d18c8.jpeg"},{"id":54319214,"identity":"8492277b-d1bc-4381-bc59-456bc4947c61","added_by":"auto","created_at":"2024-04-08 18:48:06","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":12517418,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ecGAS–STING signaling results in the detection of cytosolic DNA and is linked to the pathogenesis of CNS.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIncreased cytosolic DNA levels due to mitotic stress in cancers, cellular senescence or autoimmune disorders may lead to cGAS–STING activation and the aggravation of pathological progression. SAMHD1 functions at stalled replication forks to prevent IFN induction and has a target motif for CDK1 and a CDK-targeted motif that drives threonine 592 phosphorylation. Phosphorylation of SAMHD1 on residue T592 modulates the ability of SAMHD1 to block retroviral infection. ACE2 combined with TL4 increases the expression of the NLRP3 inflammasome, and exposure to the spike protein upregulates TLR4 signaling and the inflammasome pathway. This induction is mediated through NF-κB and p38 MAPK due to TLR4 activation. TLR4 is a critical mediator of the neurotoxicity induced by α-synuclein oligomers. α-Synuclein uptake is independent of TLR4. The cGAS–STING pathway is a significant nucleic acid recognition pathway. cGAS is an inactive protein in the cell but is activated upon binding to aberrant DNA, which results from viral invasion and senescence. cGAS forms a significant liquid‒liquid phase by clustering and separating cGAS–DNA condensates. These proteins exclude the ER-directed exonuclease TREX1. Activated cGAMP is a secondary messenger that activates the STING-dependent IFN-1 response. Activated STING translocates to the Golgi and activates TBK1, resulting in the phosphorylation of TBK1. TBK1 phosphorylates type 1 interferon regulatory factor 3 (IRF3), which then dimerizes and translocates into the nucleus, where it functions concomitantly with NF-κB, a transcription factor activated by STING. Nuclear cGAS is sequestered at chromatin in an inactive state. Activated cGAS produces cGAMP, which binds to STING. STING relocalizes to the perinuclear Golgi and forms a clustered platform where the kinase TBK1 phosphorylates the transcription factor IRF3. Along with NF-κB, phosphorylated IRF3 enters the nucleus and triggers the expression of IFN-1 and proinflammatory cytokine genes. This induces the expression of IFN-1 and inflammatory cytokines, leading to antiviral immune responses.\u003c/p\u003e","description":"","filename":"Fig51.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3849399/v2/3e89f5ac48a95e3dd1aa79d5.jpeg"},{"id":54319208,"identity":"7a58d145-7cea-451c-b93a-867a7b60e360","added_by":"auto","created_at":"2024-04-08 18:48:05","extension":"jpeg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1118571,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of adverse events of special interest (AESI) after vaccination in England and South Korea.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the graph, the X-axis represents England and South Korea, and the Y-axis represents adverse reaction cases, severe cases, anaphylaxis cases, and deaths as crude rates. The overall seroprevalence of anti-SARS-CoV-2 was very low on September 6, 2021, in South Korea. Nevertheless, the incidence of adverse events of special interest (AESI) was very high in England according to the summary of yellow card reporting by the Medicines \u0026amp; Healthcare Products Regulatory Agency (MHRA) at approximately the same time \u003csup\u003e12\u003c/sup\u003e. The spike protein of SARS-CoV-2 can induce AESI \u003csup\u003e114\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e(\u003csup\u003e∗\u003c/sup\u003e1) In the case of the UK, both anaphylaxis and anaphylaxis-like reactions are included. * It is not intended to suggest a causal relationship between an adverse reaction. Vaccination Response Promotion Team of Korea CDC, ‘21.9.6.)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e","description":"","filename":"Fig6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3849399/v2/9698bafd86ee5ca3b0be1906.jpeg"},{"id":54319213,"identity":"9c58d9db-d675-4817-89fb-f8036686c350","added_by":"auto","created_at":"2024-04-08 18:48:06","extension":"jpeg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":3869642,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThis immunological memory engineering pathway in COVID-19 pathogenesis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHuman sensory stimuli and abnormal muscular sensations affect breathing via the cerebral cortex and hypothalamus at the cortex, lung, vagal, muscle, joint, aortic arch, sensory, and central regions. The recognized immune memory pathways involve transsynaptic transfer via peripheral, olfactory, or cranial nerves. COVID-19 invades whole bodies and stimulates memory engrams in the gyri of the insula via blood–brain barrier (BBB) penetration from the systemic circulation.\u003c/p\u003e","description":"","filename":"Fig71.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3849399/v2/13894e5e557d2b077ba653a5.jpeg"},{"id":54319212,"identity":"d6b0f166-9ea9-419c-9d54-26b88b241f62","added_by":"auto","created_at":"2024-04-08 18:48:05","extension":"jpeg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":3677222,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExacerbated VRD patterns occurring over time during the endemic period and life expectancy on Sorok Island\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUpper graphs: Patients in \u003c/strong\u003eGroups 1 (T1) and 2 (T2) were diagnosed with viral respiratory disease (VRD). Patients in Group 3 (T3) and Group 4 (T4) were not diagnosed with VRD. The T1 (M = 201.47, SD = 33.86) group included VRD-diagnosed subjects prescribed dapsone, the T2 (M = 224.80, SD = 97.50) group included VRD-diagnosed subjects who were not prescribed dapsone, the T3 (M = 110.87, SD = 103.80) group included undiagnosed subjects who were prescribed dapsone, and the T4 (M = 106.13, SD = 70.30) group included undiagnosed subjects who were not prescribed dapsone. T1:T3 showed that VRD (+/-) groups treated with dapsone (+) could be distinguished as of 2010. T2: T3 graph showing that HD patients treated with dapsone have a very low prevalence of VRD. The T2:T4 test confirmed that VRD increased when the subjects were not taking dapsone \u003csup\u003e159\u003c/sup\u003e. \u003cstrong\u003eLower graphs: \u003c/strong\u003eWe included all patients taking dapsone and all individuals diagnosed with AD who were taking AADs. Then, we subtracted one from the other and processed the data as an absolute value. Factor = ㅣDDS (+) – sum AD (+) ㅣ. The acetylation-acetylcholine (AA) ratio strongly correlated with the incidence of bronchitis and COPD but not pneumonia. A gradual change in life expectancy was identified when a period of 15 years was observed (2005-2019).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e","description":"","filename":"Fig8.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3849399/v2/af9cf902e592b7dc5ebcd79c.jpeg"},{"id":80333692,"identity":"155f44d8-c5dc-41c0-a7cc-486f28e9629f","added_by":"auto","created_at":"2025-04-10 15:55:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":45365878,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3849399/v2/4a646b0a-469d-4922-817b-ee56bf4de1dc.pdf"},{"id":54319206,"identity":"da6b9a36-fbe8-4af1-95e1-0f09177858cd","added_by":"auto","created_at":"2024-04-08 18:48:05","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":56169,"visible":true,"origin":"","legend":"\u003cp\u003eSupplement fig. 1 from reference.\u003c/p\u003e","description":"","filename":"Supplement1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3849399/v2/4ead3fa04f521e27aaf4590e.docx"},{"id":54319211,"identity":"2b965803-5091-4a9a-a143-0558ef4615e0","added_by":"auto","created_at":"2024-04-08 18:48:05","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":5732335,"visible":true,"origin":"","legend":"\u003cp\u003eThe first preprint. 2022.01.14.\u003c/p\u003e","description":"","filename":"Supplement2COVID1920220114T002739.406Z.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3849399/v2/2c897c5e7c1b3187d0470332.pdf"},{"id":54319571,"identity":"b96d9f39-34d8-4b84-bbc6-9bd99e62972b","added_by":"auto","created_at":"2024-04-08 18:56:05","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":220039,"visible":true,"origin":"","legend":"\u003cp\u003eInformation disclosure request - 9318128\u003c/p\u003e","description":"","filename":"Supplement32022registrationnumber9318128.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3849399/v2/0d507ad9debc9b71efeeb28a.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eThe picture theory of seven pathways associated with COVID-19 in the real world\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated diseases. The symptoms of these patients are distributed across multiple geographical limits. Interactions between the host and virus govern induction, resulting in various consequences\u0026nbsp;\u003csup\u003e1\u003c/sup\u003e. Blood levels of cytokines during infection with COVID-19 are characterized by distinct C-reactive protein (CRP), interleukin-6 (IL-6), or triglyceride levels and significantly increased circulation\u0026nbsp;\u003csup\u003e2\u003c/sup\u003e \u003csup\u003e3\u003c/sup\u003e \u003csup\u003e4\u003c/sup\u003e \u003csup\u003e5\u003c/sup\u003e \u003csup\u003e6\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe pathophysiologic mechanisms include direct toxicity through virus-dependent means, including invasion of alveolar epithelial and endothelial cells by SARS-CoV-2 and microvascular endothelial injury. Other virus-induced indirect conditions might be encountered during infection in the elderly with dementia drugs, such as immunological damage by suppressed muscarinic receptor and a dysregulated hyperinflammatory state, including perivascular inflammation and hypercoagulability with resultant thrombotic occlusions, effects on the renin-angiotensin-aldosterone system (RAAS), and the endothelium as well as maladaptation to the angiotensin-converting enzyme 2 (ACE2) pathway\u0026nbsp;\u003csup\u003e7\u003c/sup\u003e. Hypercoagulability and hyperinflammation may favor stroke via microvascular circulation abnormalities, microthrombus formation, and multifocal lesions\u0026nbsp;\u003csup\u003e8\u003c/sup\u003e. This pathological combination contributes to the breakdown of the endothelial\u0026ndash;epithelial barrier\u0026nbsp;\u003csup\u003e9\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSeven pathways and\u0026nbsp;a novel excess acetylcholine pathway describe acute kidney injury, hepatic, cardiac, neurological, and gastrointestinal injury: acute coronary syndrome, myocarditis, arrhythmia, Takotsubo cardiomyopathy, stroke, encephalopathy, anosmia, transaminitis, diarrhea, nausea, vomiting, and anorexia\u0026nbsp;\u003csup\u003e10\u003c/sup\u003e. We have vigilantly monitored for underlying conditions. Our study describes the important molecular pathways associated with SARS-CoV-2 infection and provides detailed descriptions of pathological metabolic pathways based on eight tracks.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFor 2023, two years after 2021, we checked the final experimental results and found that they matched precisely within the seven pathways. The experimental results for 2022 and 2023 are underlined along with the cited papers. Papers published before 2020 were excluded from the analysis. Only papers published from 2020 to 2024 are described (Table 1).\u003c/p\u003e\n\u003cp\u003e1. Of the eight papers cited on the ACE2 and TLR pathways, five were used, and three were not used. Six papers were added to the last version. Nineteen papers were added that described ACE2, TLRs, and inflammasome activation. Six papers were rediscovered between 2022 and 2023.\u003c/p\u003e\n\u003cp\u003e2. In the neuropilin‑1 pathway, all seven cited papers were used. Twenty-four papers were successive. Papers 54 and 58 were added while explaining the engrams. These findings provide insight into the distribution of NRP1 in brain cells. It was rediscovered by seven papers between 2022 and 2023.\u003c/p\u003e\n\u003cp\u003e3. In the SAMHD1 tetramerization pathway, two papers were used. Twelve papers were successive. Papers 64 and 81 were added while explaining the characteristics of the inflammatory response and IFN action caused by the spike protein. These findings were rediscovered by seven papers dated from 2022-2023.\u003c/p\u003e\n\u003cp\u003e4. In the inflammasome activation pathway, three of the five cited papers were still used. Paper 204 was not used, and paper 117 was used to explain why the spike protein activates the inflammasome. Thirteen papers were successive to the last version, and the findings were rediscovered by six papers from 2022-2023.\u003c/p\u003e\n\u003cp\u003e5. In the cGAS\u0026ndash;STING signaling pathway, three of the six cited papers were still used. Papers 206 and 207 were not used, and paper 119 went on to explain the generation of an immune response by the spike protein. Eleven papers were published successively, and the findings were rediscovered by five papers from 2022-2023.\u003c/p\u003e\n\u003cp\u003e6. In the spike protein pathway, seven out of fourteen papers were continuously used. Papers 210, 211, 212, and 213 were not used; paper 16 went on to explain the mechanism by which ACE2 activates the inflammasome; and papers 64 and 81 went on to describe SAMHD1, which prevents virus invasion. Twenty-three papers were successive, 117 of which explained the inflammasome and 119 of which explained the cGAS\u0026ndash;STING inflammasome; these findings were rediscovered by eight papers from 2022-2024.\u003c/p\u003e\n\u003cp\u003e7. In the immunological memory engram pathway, nine out of the thirteen papers were continuously used. Papers 214 and 215 were not used, and papers 54 and 58 were used to explain the clinical correlation between NRP1 in the brain and ARDS in the lung. Eighteen papers were published, and the findings were rediscovered by five papers published between 2022 and 2024.\u003c/p\u003e\n\u003cp\u003e8. Three papers were added to the excess acetylcholine pathway in 2022, and new results were rediscovered by nine papers from 2022-2023.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003cstrong\u003e. ACE2 and TLR pathways\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe life cycle of SARS-CoV-2 begins after binding to ACE2 in the epithelium of the oral mucosa, lung, heart, and kidney, and the expression of ACE2 increases with age\u0026nbsp;\u003csup\u003e11\u003c/sup\u003e \u003csup\u003e12\u003c/sup\u003e. Smoking affects ACE2 expression and induces mineral dust‑induced gene (MDIG) expression, which alters the transcription of several essential proteins implicated in exacerbating COVID-19\u0026nbsp;\u003csup\u003e13\u003c/sup\u003e \u003csup\u003e14\u003c/sup\u003e. This type of epigenetic gene expression alters gene locus function without changing the underlying DNA sequence. Instead, it relies on posttranslational chemical changes in chromatin, RNA, and DNA. These changes include acetylation, methylation, phosphorylation, ubiquitination and SUMOylation. These changes are linked to genotype and phenotype\u0026nbsp;\u003csup\u003e15\u003c/sup\u003e.\u0026nbsp;The interaction of ACE2 with the SARS-CoV-2 spike protein (SP) in tiny numbers of embryonic-like stem cells (VSELs) and hematopoietic stem cells (HSCs) activates the NLR family PYRIN domain containing-3 (NLRP3) inflammasome. The exposure of human umbilical cord blood (UCB)-purified VSELs to recombinant SP can lead to the upregulation of NLRP3 mRNA expression\u0026nbsp;\u003csup\u003e16\u003c/sup\u003e. Human VSELs in adult tissues can be damaged by SARS-CoV-2, which has\u0026nbsp;downstream and subsequent\u0026nbsp;effects on tissue/organ regeneration\u0026nbsp;\u003csup\u003e16\u003c/sup\u003e. SARS-CoV-2 activates mitochondrial reactive oxygen species (ROS) production and glycolytic shift. SP alone can damage vascular endothelial cells by downregulating ACE2 and inhibiting mitochondrial function\u0026nbsp;\u003csup\u003e17\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eACE2 and Toll-like receptor 4 (TLR4, CD284) on the cell surface belong to the pattern recognition receptor (PRR) family. ACE2 and TLR4 are highly expressed in hematopoietic stem and progenitor cells. These cells are highly susceptible to SP. ACE2 and TLR4 produce inflammatory cytokines and activate innate immune responses. Erythroid precursor cells (from CD 34\u003csup\u003e+\u003c/sup\u003e) differentiate into red blood cell (RBC) precursors and subsequently express ACE2. The SARS-CoV-2 SP interacts with RBC precursors, leading to dysregulation of hemoglobin and degradation of Fe-heme\u0026nbsp;\u003csup\u003e18\u003c/sup\u003e \u003csup\u003e19\u003c/sup\u003e. Blocking the interaction of SP with cell surface-expressed ACE2 and TL4 decreased the activation of the downstream mediator of NLRP3, caspase-1. This suppression was even more noticeable after blocking the interaction of the SP with both receptors. Exposure to SP\u0026nbsp;upregulates the expression of proteins participating in the positive stimulation of the TLR4 signaling pathway\u0026nbsp;\u003csup\u003e18\u003c/sup\u003e. The SP has been proposed to have the most substantial protein‒protein interaction with TLR4. TLR2 and TLR4 are expressed intracellularly in dendritic, epithelial, and endothelial cells\u0026nbsp;\u003csup\u003e20\u003c/sup\u003e \u003csup\u003e21\u003c/sup\u003e. The molecular influence of TLR4 is understood as a prime regulatory factor associated with immunity\u0026nbsp;\u003csup\u003e22\u003c/sup\u003e. TLR4 mediates anti-gram-negative bacterial immune responses by recognizing lipopolysaccharide (LPS) from bacteria\u0026nbsp;\u003csup\u003e23\u003c/sup\u003e. \u003cem\u003eStaphylococcus aureus\u003c/em\u003e triggers an inflammatory response in innate immune cells via TLR4 and the inflammasome\u0026nbsp;\u003csup\u003e24\u003c/sup\u003e. SARS-CoV-2 infection results in viral sepsis and provokes an antibacterial-like response at the very early stage of infection via TLR4\u0026nbsp;\u003csup\u003e25\u003c/sup\u003e (\u003cstrong\u003eFig. 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eTLRs are a class of membrane pattern recognition receptors that detect microbes on the cell surface and in the cytoplasm, and a cytokine surge is induced by TLRs, mainly through the activation of TLR3, TLR4, TLR7, and TLR8\u003csup\u003e26\u003c/sup\u003e. Subunit 1 of the\u0026nbsp;SARS-CoV-2 spike protein (S1) induces sickness behavior and a subacute neuroinflammatory response for approximately 24 hours and a chronic neuroinflammatory response for approximately 7 days. Moreover, S1 directly induces a proinflammatory response in primary microglia and activates TLR4 signaling\u0026nbsp;\u003csup\u003e27\u003c/sup\u003e. Neuroinflammation induced by microglia is mediated through the activation of nuclear factor kappa B (NF-\u0026kappa;B) and p38 mitogen-activated protein kinase (MAPK) due to TLR2 and TLR4 activation\u0026nbsp;\u003csup\u003e26\u003c/sup\u003e \u003csup\u003e27\u003c/sup\u003e \u003csup\u003e28\u003c/sup\u003e. TLR4 has been shown to play a role in mediating the neurotoxicity induced by \u0026alpha;-synuclein (\u0026alpha;-Syn)\u0026nbsp;oligomers. Misfolded\u0026nbsp;\u0026alpha;-Syn\u0026nbsp;induces inflammatory responses; however,\u0026nbsp;\u0026alpha;-Syn\u0026nbsp;uptake is independent of TLR4. Furthermore, extracellular\u0026nbsp;\u0026alpha;-Syn\u0026nbsp;can activate the proinflammatory TLR4 pathway in astrocytes\u0026nbsp;\u003csup\u003e29\u003c/sup\u003e. The interaction between the SARS-CoV-2 SP and TLR4 can trigger an intracellular TLR4 signaling cascade. The NF-\u0026kappa;B-mediated transcriptional activation of specific genes induces the release of proinflammatory cytokines, which can damage neurons and pathologically modify\u0026nbsp;\u0026alpha;-Syn\u0026nbsp;\u003csup\u003e30\u003c/sup\u003e. The final sequence of NF-\u0026kappa;B activation involves a range of cytokine receptor- and TLR-mediated signaling cascades. SARS-CoV-2 induces TLR4-mediated NF-\u0026kappa;B activation, and erythroreticulum (ER) stress induces NF-\u0026kappa;B activation and the production of immature IL-1\u0026beta; (pro-IL-1\u0026beta;)\u0026nbsp;\u003csup\u003e31\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eThe neuropilin‑1 pathway\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNeuropilin-1 (NRP1) is a pleiotropic single-transmembrane coreceptor for class 3 semaphorins and vascular endothelial growth factors. Along with ACE2, NRP1 facilitates the entry of SARS‑CoV‑2 into host cells. NRP1 is a highly conserved transmembrane receptor lacking a cytosolic protein kinase domain\u0026nbsp;\u003csup\u003e32\u003c/sup\u003e \u003csup\u003e33\u003c/sup\u003e. In combination with host\u0026nbsp;transmembrane protease serine 2 (TMPRSS2), SARS-CoV-2 uses the ACE2 receptor for cell entry, which cleaves the viral spike glycoprotein\u0026nbsp;\u003csup\u003e34\u003c/sup\u003e \u003csup\u003e35\u003c/sup\u003e. The expression of ACE2 and NRP1 with TMPRSSs has been observed in various human tissues and organs, thus facilitating viral activation and representing the essential host factors for SARS-CoV-2 pathogenicity. These viruses contribute to the tropism of SARS-CoV-2 in diverse tissues and organs and its related symptoms\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNRP1 is expressed in all vertebrates. NRP1 is the primary coreceptor for ACE2. NRP1 contributes to the primary tissue or organ tropism of SARS-CoV-2. NRP1 and 2 are involved in angiogenesis, axon control, cell proliferation, immune function, neuronal development, and vascular permeability because NRP1 is a coreceptor for vascular endothelial growth factors\u0026nbsp;\u003csup\u003e36\u003c/sup\u003e.\u0026nbsp;NRP1 plays a complex role in the secondary CD8+ T-cell response to control VRDs and tumors\u0026nbsp;\u003csup\u003e37\u003c/sup\u003e.\u0026nbsp;A complete understanding of NRP1 or NRP2 and its associated mechanical pathways will facilitate understanding of SARS-CoV-2 infectivity and improve patient treatments; however, ACE2 is the primary receptor for entry of SARS-CoV-2 into cells\u003cstrong\u003e\u0026nbsp;(Fig. 2)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eThe genetic susceptibility locus in respiratory failure patients with COVID-19 is located on chromosomes 3p21.31 and 9q34.2 and is related to severity; the 3p21.31 gene cluster can be found on chromosome 3\u0026nbsp;\u003csup\u003e38\u003c/sup\u003e. The risk locus is inherited from Neanderthals, which are segmented by a genomic size of approximately 50 kilobases, and there is no evidence that genetic haplotypes progressed from Neanderthals into African populations\u0026nbsp;\u003csup\u003e31\u003c/sup\u003e. According to the protein docking crystal structures, the receptor binding domain (RBD) of the SARS-CoV-2 spike protein has a potentially high affinity for dipeptidyl peptidase-4 (DPP4). The present genetic variants from a Neanderthal heritage plant were located in six genes on chromosome 3p21.31, which is in the proximal promoter region of DPP4. The DPP4 gene encodes the enzyme dipeptidyl peptidase IV. Dipeptidyl peptidase IV serves as a receptor for MERS-CoV\u0026nbsp;\u003csup\u003e39\u003c/sup\u003e, but a genetic variant in the promoter region of the DPP4 gene has been shown to double the risk of developing critical COVID-19 pathogenesis. Moreover, DPP9, a homolog of DPP4, was significantly associated with severe COVID-19. These findings suggested a potential role for DPP4 in COVID-19\u0026nbsp;\u003csup\u003e40\u003c/sup\u003e. A haplotype on chromosome 12 from Neanderthals is associated with an approximately 22% decrease in the relative risk of developing severe illness\u0026nbsp;\u003csup\u003e41\u003c/sup\u003e. MDIGs are mainly responsible for the expression of inflammatory cytokines, the critical component of the inflammasome, and most of the genes involved in glycan metabolism for hyaluronan generation and glycosylation. MIDGs are crucial determinants of viral infection and cytokine storms\u0026nbsp;\u003csup\u003e42\u003c/sup\u003e. MDIG is an environmentally induced lung cancer oncogene whose entry into MDA-MB-231 and A549 cells depends on NRP1 and NRP2 expression in the cell membrane\u0026nbsp;\u003csup\u003e42\u003c/sup\u003e. MDIG is also an essential regulator of NRP1 and NRP2. In MDIG knockout cells, researchers observed strong H3K9me3 and H4K20me3 upstream of the DPP4 gene from the Neanderthal haplotype region at chromosome 3p21.31 and chromosome 2q24.2 on the proximal promoter region of DPP4, which is another Neanderthal variant gene\u0026nbsp;\u003csup\u003e42\u003c/sup\u003e. Moreover, these effects are attributable to pulmonary fibrosis in some COVID-19 survivors. Among patients with a history of environmental exposure, MDIG plays a critical role in preventing SARS-CoV-2 infection and reducing the severity of COVID-19. The MDIG-dependent expression of NRP1 or NRP2 enhances SARS-CoV-2 infection in cells with lower ACE2 expression\u0026nbsp;\u003csup\u003e42\u003c/sup\u003e. Knockout of MDIG does not affect the enrichment of the repressive histone trimethylation markers H3K9me3, H3K27me3, or H4K20me3 on the protective Neanderthal haplotypes on chromosome 12, which reduces the risk of exacerbating COVID-19\u0026nbsp;\u003csup\u003e41\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eNRP1 is a tissue-specific marker of lung 2 ILC2s and is induced postnatally and sustained by lung-derived transforming growth factor-\u0026beta;1 (TGF\u0026beta;1). TGF\u0026beta;1\u0026ndash;NRP1 signaling enhances ILC2 functions and type 2 immunity, suggesting that NRP1 is a tissue-specific regulator of lung-resident ILC2s and that the NRP1 regulator is a potential therapeutic agent for pulmonary fibrosis\u0026nbsp;\u003csup\u003e43\u003c/sup\u003e. In addition, NRP1 and NRP2 support competent viral entry into host cells in the lung. MDR complex access to two additional cell lines (MDA-MB-231 and A549) depends on NRP1 and NRP2. Moreover, MDIG has a role in preventing SARS-CoV-2 infection and reducing the severity of COVID-19 in patients who are experiencing environmental exposure to toxins. These effects explain the observed pulmonary fibrosis in some COVID-19 survivors; MDIG-dependent expression of NRP1 or NRP2 increases SARS-CoV-2 infection despite reduced ACE2 expression\u0026nbsp;\u003csup\u003e42\u003c/sup\u003e. ILC2s are involved in virus-induced exacerbation of airway inflammation and are critical in pulmonary fibrosis and autoimmune disease\u0026nbsp;\u003csup\u003e44\u003c/sup\u003e \u003csup\u003e45\u003c/sup\u003e. Human ILC2s are flexible and adapt to the cytokine microenvironment by changing cytokine outputs to meet existing requirements\u0026nbsp;\u003csup\u003e46\u003c/sup\u003e. ILC2s and eosinophils play vital roles in pulmonary arterial hypertrophy\u0026nbsp;\u003csup\u003e47\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eGroup 3 ILCs (ILC3s)\u0026nbsp;produce greater amounts of cytokines than ILC3s that do not express NRP1. NRP1\u003csup\u003e+\u003c/sup\u003e ILC3s are present in fetal tissues and ectopic lymphoid aggregates and play a role in inflammation and vascularization\u0026nbsp;\u003csup\u003e48\u003c/sup\u003e. SARS-CoV-2 targets ciliated cells in the respiratory mucosa, but in the olfactory mucosa, the primary target is nonneuronal sustentacular cells. NRP1 is expressed in olfactory‑related neuronal regions\u0026nbsp;\u003csup\u003e49\u003c/sup\u003e \u003csup\u003e50\u003c/sup\u003e.\u0026nbsp;Compared with other brain regions, SARS-CoV-2 may exhibit tropism to the brainstem, which has relatively high expression of the ACE2 receptor\u0026nbsp;\u0026nbsp;\u003csup\u003e32\u003c/sup\u003e \u003csup\u003e33,51\u003c/sup\u003e \u003csup\u003e52\u003c/sup\u003e. The recognized pathways involve transsynaptic transfer via peripheral, olfactory, or cranial nerves and blood‒brain barrier (BBB) penetration from the systemic circulation to invade the brainstem\u0026nbsp;\u003csup\u003e51\u003c/sup\u003e \u003csup\u003e52\u003c/sup\u003e \u003csup\u003e53\u003c/sup\u003e. The recognized pathways invade the brainstem and involve transsynaptic transfer via peripheral, olfactory, or cranial nerves (\u003cstrong\u003eFig. 3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eClinically, COVID-19-related\u0026nbsp;acute respiratory distress syndrome (ARDS) is characterized by relatively preserved aeration on chest computed tomography (CT) despite severe respiratory hypoxemia. However, this early, high-compliance phenotype can develop into a low-compliance phenotype with poor aeration as L-type, characterized by low elastance, high compliance, and preserved aeration; and H-type, characterized by high elastance, low compliance, and poor aeration\u0026nbsp;\u003csup\u003e54\u003c/sup\u003e.\u0026nbsp;Patients with cryptococcus-associated immune reconstitution inflammatory syndrome can suffer from pulmonary dysfunction caused by T-cell-driven neurodegeneration in the vital medullary nucleus responsible for respiratory control\u0026nbsp;\u003csup\u003e55\u003c/sup\u003e \u003csup\u003e56\u003c/sup\u003e. The paralysis of the pre-B\u0026ouml;tzinger complex on the medullar oblongata in the brainstem might affect L-type ARDS and COVID-19-associated fatality\u0026nbsp;\u003csup\u003e57\u003c/sup\u003e. NRP-1 might induce the tropism of SARS-CoV-2 in the brainstem\u0026nbsp;\u003csup\u003e51\u003c/sup\u003e \u003csup\u003e57\u003c/sup\u003e \u003csup\u003e58\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eThe SAMHD1 tetramerization pathway\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVRDs produce interferon (IFN)-1, which exacerbates their pathological course, but interferon treatment reduces inhibitory M2 muscarinic receptor function\u0026nbsp;\u003csup\u003e59\u003c/sup\u003e. The genesis of the acetylcholine (ACh) receptor requires interferon\u0026nbsp;\u003csup\u003e60\u003c/sup\u003e. Muscarinic and nicotinic ACh receptors regulate immune function\u0026nbsp;\u003csup\u003e61\u003c/sup\u003e. The sterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein 1 (SAMHD1) operate at stalled replication forks to prevent the induction of IFN, a significant regulator of deoxynucleotide triphosphate (dNTP) concentrations in human cells\u0026nbsp;\u003csup\u003e62\u003c/sup\u003e.\u0026nbsp;The concentrations of dNTPs, substrates for DNA-polymerizing enzymes, are limited in cells. However, SAMHD1 is a\u0026nbsp;deoxyribonucleotide triphosphate triphosphohydrolase (dNTPase) that cleaves dNTPs to deoxynucleosides and triphosphates. The induction of SAMHD1 in differentiated cells requires low levels of dNTPs in nonproliferating cells to mediate DNA repair and maintain mitochondria. High dNTP levels can cause problems in maintaining mitochondrial function, which might occur in\u0026nbsp;Aicardi\u0026ndash;Gouti\u0026egrave;res syndrome\u0026nbsp;(AGS) patients. This genetic inflammatory encephalopathy resembles congenital viral infections and certain autoimmune disorders. AGS mutations in the SAMHD1 gene reduce catalytic activity or allosteric activation by dGTP. They also increase intracellular dNTP levels. These mutations may contribute to the dysfunctional differentiation of innate immune cells. The phenotype of SAMHD1 mutations is consistent with that of AGS, which increases dNTP levels. This could lead to a more robust viral infection because of the loss of the dNTP triphophohydrolase activity of SAMHD1. Viruses can replicate their viral genome with their polymerase\u0026nbsp;\u003csup\u003e63\u003c/sup\u003e. Elevated intracellular levels of dNTPs are biochemical markers of cancer cells. Many multifunctional dNTPase and SAMHD1 mutations have been reported in various cancers. The SAMHD1 R366C/H mutant has been found in colon cancer and leukemia, as shown in Supplemental Fig. 1 of Supplement 1\u0026nbsp;\u003csup\u003e64\u003c/sup\u003e.\u0026nbsp;R366C/H mutants retain dNTPase-independent functions, such as mediating dsDNA break repair, interacting with C-terminal binding protein 1 interacting protein (CtIP) and cyclin A2, and suppressing innate immune responses. The SAMHD1 R366 mutation does not alter the cellular protein levels of the enzyme but does inhibit the dNTPase activity and nucleotide density at the catalytic site on the X-ray structure. R366C/H does not restrict HIV-1 replication, which is a function of SAMHD1 that is dependent on the ability to hydrolyze dNTPs\u0026nbsp;\u003csup\u003e64\u003c/sup\u003e.\u0026nbsp;SAMHD1 negatively regulates the IFN-1 signaling pathway, and genetic loss of SAMHD1 elevates the innate immune response and IFN activation.\u0026nbsp;The antiviral IFN responses induced by SAMHD1 suppressed SARS-CoV-2 replication and elevated cellular innate immunity\u0026nbsp;\u003csup\u003e65\u003c/sup\u003e. Suppressing innate immune responses is essential for the survival of SARS-CoV-2 and HIV-1. Viral protein X (Vpx)\u0026nbsp;performs several functions during infection, including downregulating SAMHD1\u0026nbsp;\u003csup\u003e66\u003c/sup\u003e \u003csup\u003e67\u003c/sup\u003e \u003csup\u003e68\u003c/sup\u003e. This function of Vpx is conserved among the HIV-2/simian immunodeficiency virus (SIV) accessory protein Vpx\u0026nbsp;\u003csup\u003e69\u003c/sup\u003e. The lentiviral Vpx variant suppresses SARS-CoV-2 RNA expression in primary human monocyte\u0026ndash;derived macrophages\u0026nbsp;\u003csup\u003e65\u003c/sup\u003e. Moreover, Vpx inhibits STING signalosomes and interferes with the nuclear translocation of NF-\u0026kappa;B and the induction of innate immune genes\u0026nbsp;\u003csup\u003e68\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eMutations in the Aicardi\u0026ndash;Gouti\u0026egrave;res syndrome protein SAMHD1 are implicated in the pathogenesis of chronic lymphocytic leukemia (CLL) and AGS. SAMHD1 has a target motif for cyclin-dependent kinase 1 (CDK1) (\u003csup\u003e592\u003c/sup\u003eTPQK\u003csup\u003e595\u003c/sup\u003e: the CDK-targeted motif driving threonine 592 (T592) phosphorylation)\u0026nbsp;\u003csup\u003e70\u003c/sup\u003e.\u0026nbsp;CDKs are protein kinases that play key roles in cell division, transcriptional regulation, and viral infections\u0026nbsp;\u003csup\u003e71\u003c/sup\u003e. SARS-CoV-2 infection triggers and redistributes cyclin D1 and D3 from the nucleus to the cytoplasm and subsequent proteasomal degradation. Cyclin D3 prevents the efficient incorporation of the envelope protein into virions during assembly. Its degradation during SARS-CoV-2 infection relieves cyclin interference with virion assembly\u0026nbsp;\u003csup\u003e72\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003ePhosphorylation of SAMHD1\u0026nbsp;at residue T592 modulates the ability of SAMHD1 to block retroviral infection, but SAMHD1 can still decrease cellular dNTP levels\u003csup\u003e70\u003c/sup\u003e. A phosphomimetic environment\u0026nbsp;mimics the phosphorylation of amino acid substitutions. A\u0026nbsp;distinct negatively charged T592\u0026nbsp;phosphomimetic mutation\u0026nbsp;generates electrostatic repulsive movement and reduces the stability of the SAMHD1 tetramer and the dNTPase activity of the enzyme. This repulsive electrostatic phosphorylation allosterically decreases dNTPase activity and may modify antiviral functions\u0026nbsp;\u003csup\u003e73\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eSAMHD1 forms tetramers of GTP, and all four dNTPs are controlled by the combined action and inactive apo-SAMHD1 interconverts between monomers and dimers. The binding of dGTP to four allosteric sites stimulates and causes a conformational change in the substrate-binding pocket, which results in a catalytically active tetramer\u0026nbsp;\u003csup\u003e74\u003c/sup\u003e. The binding sites can adjust oligonucleotides instead of the allosteric activators GTP and dNTPs. The G-nucleotides containing oligonucleotides form a specific tetramer with mixed occupancy of the allosteric sites in the presence of GTP and dNTPs. Plastic and allosteric nucleic acid binding promotes the immunomodulatory effects of the antiretroviral activity of SAMHD1\u0026nbsp;\u003csup\u003e75\u003c/sup\u003e. SAMHD1 can restrict retroviruses and protect cells from viral infections by catalyzing the hydrolysis of dNTPs in the dNTP pool. SAMHD1 depletes intracellular dNTPs into 20-deoxynucleoside and triphosphate products\u0026nbsp;\u003csup\u003e70\u003c/sup\u003e \u003csup\u003e76\u003c/sup\u003e. cell autonomous control of lentivirus infection in myeloid cells by SAMHD1 limits virus-induced production of IFNs and the induction of costimulatory markers. SAMHD1 autonomously controls viral infection through innate and adaptive immunity at the level of the infected cell. SAMHD1 limits lentivirus-induced IFN production in myeloid cells and reduces the induction of virus-specific cytotoxic T cells\u0026nbsp;\u003csup\u003e77\u003c/sup\u003e. SAMHD1 mutations result in autoinflammatory AGS, and AGS secretes chronic IFN-I despite the absence of viral infections; moreover, this disease is characterized by early-stage brain disease\u0026nbsp;\u003csup\u003e78\u003c/sup\u003e \u003csup\u003e79\u003c/sup\u003e \u003csup\u003e80\u003c/sup\u003e. SARS-CoV-2 encounters a response that requires the strong induction of a subclass of cytokines, including IFN-I, IFN-III, and a few chemokines\u0026nbsp;\u003csup\u003e80\u003c/sup\u003e. The SAMHD1 tetramer structure could provide a mechanistic understanding of its rapid function in SARS-CoV-2 pathogenesis. SANHD1-deficient cells detect and activate\u0026nbsp;IFN-I-mediated antiviral gene expression in HIV-1 cells via cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) (cGAS\u0026ndash;STING)\u0026nbsp;\u003csup\u003e79\u003c/sup\u003e.\u0026nbsp;cGAS\u0026ndash;STING is decreased during radiotherapy in cancer patients but promptly recovers after radiotherapy. SAMHD1, which suppresses viral replication and viral response genes, occurs more frequently in severe ventilation-associated COVID-19 patients than in nonventilated patients, and\u0026nbsp;we observed important treatment-related alterations, specifically IFN-I responses.\u0026nbsp;\u003csup\u003e81\u003c/sup\u003e. The degradation of SAMHD1 in human primary-activated/dividing CD4+ T cells, the increase in cellular dNTP levels, and the loss of dNTPase activity contribute to the increase in commonly observed dNTP levels\u0026nbsp;\u003csup\u003e64\u003c/sup\u003e. SARS-CoV-2 aggravates a reaction in which SAMHD1 controls the innate immune response\u0026nbsp;\u003csup\u003e65\u003c/sup\u003e. SAMHD1 in cells inhibits NF-\u0026kappa;B activation and IFN-I induction\u0026nbsp;\u003csup\u003e82\u003c/sup\u003e. Therefore, low levels of IFN-I could drive more severe SARS‐CoV‐2 infection\u0026nbsp;\u003csup\u003e83\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eInflammasome activation pathway\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe NLRP3 inflammasome contains NLRP3 as a sensor protein, ASC as an adaptor protein, and caspase-1 as an effector protein. The NLRP3 protein has three domains: 1. the pyrin domain (PYD), 2. the nucleotide-binding domain, and 3. the leucine-rich repeat domain. PYD interacts with apoptosis-associated speck-like protein with the caspase recruitment domain (ASC) PYD and subsequently promotes ASC oligomer formation. The ASC platform induces caspase-1 activation, which catalyzes the conversion of pro-IL-1\u0026beta; to mature IL-1\u0026beta;. NLRP3 deubiquitination and self-aggregation occur after ASC recruitment and oligomerization. Active caspase-1 cleaves pro-IL-1\u0026beta; and pro-IL-18 into mature IL-1\u0026beta; and IL-18, respectively. Excessive IL-1\u0026beta; activates various signaling pathways, such as the NF-\u0026kappa;B and Jun N-terminal kinase (JNK) signaling pathways, and as a result, it stimulates systemic inflammatory responses. IFN-\u0026alpha;, IFN-\u0026beta;, IL-6, tumor necrosis factor (TNF), and TGF\u0026beta;1 can lead to cytokine storms. The SARS-CoV-2 genome is enclosed by a nucleocapsid\u0026nbsp;(N) protein in\u0026nbsp;phospholipid bilayers. The membrane and envelope proteins are located among the SPs in the virus envelope. There are four main types of inflammasomes, NLRP1, NLRP3, NLRC4, and AIM2, which are classified after being regarded as distinct sensing proteins. Inflammasomes consist of at least three components: the inflammasome caspase (caspase-1, Caspase-4/11), an adapter molecule (ASC), and a sensor/receptor protein (NLRP1, NLRP3, NAIP1/2/5, NLRP12, AIM2, etc.)\u0026nbsp;\u003csup\u003e84\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eActive the NLRP3 inflammasome were found in tissues and peripheral blood mononuclear cells (PBMCs) from postmortem patients with moderate or severe COVID-19. The serum levels of IL-6, LDH, caspase-1, caspase-4/11, and IL-18 are correlated with disease severity. Moreover, higher Caspase-1, Caspase-4/11, and IL-18 levels are associated with poor clinical outcomes\u0026nbsp;\u003csup\u003e85\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eSARS-CoV-2 causes pyroptosis in human monocytes. Pyroptosis is associated with caspase-1, caspase-4/11, interleukin 1\u0026beta; (IL-1\u0026beta;), and gasdermin D expression and cytokine levels in primary monocytes\u0026nbsp;\u003csup\u003e86\u003c/sup\u003e \u003csup\u003e87\u003c/sup\u003e. SARS-CoV-2 engages in Caspase 4/11-mediated noncanonical activation of NLRP3 and contributes to COVID-19 exacerbation\u0026nbsp;\u003csup\u003e87\u003c/sup\u003e. When recombinant baculoviruses displaying SP or nucleocapsid (N) protein were constructed and transfected into lung epithelial A549 cells and a spontaneously immortalized monocyte-like cell line (THP-1)-derived macrophages,\u0026nbsp;the\u0026nbsp;N protein triggered A549 cells to release more serum cytokines than did the SP\u0026nbsp;\u003csup\u003e88\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eBlocking the NLRP3 inflammasome reduces the cytokine storms and lung injury caused by SARS-CoV-2 infection. The N protein facilitated ASC oligomerization by increasing the interaction between NLRP3 and ASC. The N protein, NLRP3, and ASC form a complex and activate the NLRP3 inflammasome\u0026nbsp;\u003csup\u003e89\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe SARS-CoV-2 ORF10 targets STING, attenuates the STING-TBK1 association, and impairs STING oligomerization, aggregation, and autophagy (\u003cstrong\u003eFig. 4\u003c/strong\u003e). It impairs cGAS\u0026ndash;STING-TBK1 signaling and antagonizes STING-dependent IFN activation and autophagy\u0026nbsp;\u003csup\u003e90\u003c/sup\u003e. ORF9b and nonstructural protein 7 (NSP7) antagonize the production of type I and III IFNs by targeting the retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5), TLR3-TIR-domain-containing adapter-inducing interferon-\u0026beta; (TRIF), and cGAS-STING signaling pathways\u0026nbsp;\u003csup\u003e91\u003c/sup\u003e \u003csup\u003e92\u003c/sup\u003e. The expression of NSP7 blocks innate immune activation and facilitates virus replication\u0026nbsp;\u003csup\u003e93\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe detection of cytosolic DNA (cDNA) via the cGAS\u0026ndash;STING axis induces a cell death program that initiates potassium efflux upstream of NLRP3. The combination of NLRP3 with cGAS-STING constitutes the primary inflammasome response during viral and bacterial infections in human myeloid cells and ameliorates the pathology of inflammatory conditions linked with cDNA sensing\u0026nbsp;\u003csup\u003e94\u003c/sup\u003e. Microglial NLRP3 inflammasome activation is a major driver of neurodegeneration\u0026nbsp;\u003csup\u003e95\u003c/sup\u003e \u003csup\u003e96\u003c/sup\u003e \u003csup\u003e97\u003c/sup\u003e\u003csup\u003e,,\u003c/sup\u003e and purified SP activated the NLRP3 inflammasome in LPS-primed microglia in an ACE2-dependent manner\u0026nbsp;\u003csup\u003e98\u003c/sup\u003e.\u0026nbsp;In addition, mitochondrial antiviral signaling protein (MAVS) connects with NLRP3 and controls its inflammasome activity\u0026nbsp;\u003csup\u003e99\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ecGAS\u0026ndash;STING signaling pathway\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSARS-CoV-2, an RNA virus, activates the\u0026nbsp;cDNA\u0026nbsp;sensor cGAS\u0026ndash;STING signaling in endothelial cells. The cGAS-STING pathway controls immunity to\u0026nbsp;cDNA\u0026nbsp;and drives aberrant IFN-I responses in patients with COVID-19\u0026nbsp;\u003csup\u003e100\u003c/sup\u003e. Mitochondrial DNA is released and leads to IFN-I production. Blocking STING reduces severe lung inflammation, but a STING agonist also protects against SARS-CoV-2 infection\u003csup\u003e100\u003c/sup\u003e \u003csup\u003e101\u003c/sup\u003e.\u0026nbsp;cGAS catalyzes the conversion of\u0026nbsp;cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) to\u0026nbsp;cDNA. It triggers STING\u0026ndash;tank-binding kinase 1 (TBK1)\u0026ndash;interferon regulatory factor 3 (IRF3) signaling\u0026nbsp;\u003csup\u003e102\u003c/sup\u003e. cGAS also appears in the nucleus, where cGAS in an inactive state is isolated\u0026nbsp;from chromatin. Nuclear cGAS recruits protein arginine methyltransferase 5 (PRMT5) upon viral infection. In innate immunity, nucleus-localized cGAS interacts with PRMT5 to catalyze the symmetric dimethylation of histone H3 arginine 2 at IRF3-responsive genes, such as interferon beta 1 (IFN\u0026beta;1)\u0026nbsp;and interferon alpha 4 (IFN\u0026alpha;4). As a result, PRMT5 facilitates\u0026nbsp;IRF3 access\u0026nbsp;\u003csup\u003e103\u003c/sup\u003e.\u0026nbsp;Activated cGAS releases cGAMP, which binds to STING; thus, STING relocalizes and forms a clustered platform at the perinuclear Golgi. The kinase TBK1 phosphorylates IRF3, and IRF3 then enters the nucleus. Moreover, NF-\u0026kappa;B triggers the expression of IFN-1 and proinflammatory cytokine genes\u0026nbsp;\u003csup\u003e104\u003c/sup\u003e \u003csup\u003e105\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eSevere COVID-19-related\u0026nbsp;inflammation is associated with excessive lung tissue damage and syncytial pneumocyte formation. Cultured epithelial cells expressing ACE2 and SP formed multinucleated syncytial cells. The fused cells exhibited DNA damage and micronuclei expressing cGAS-STING, which colocalized with and stimulated IFNs and IFN-stimulated genes\u0026nbsp;\u003csup\u003e106\u003c/sup\u003e. The useful cellular functions of cGAS-STING are mediated by canonical and a few noncanonical pathways, but dysfunction of cGAS-STING-mediated cellular functions and noncanonical signaling underlie disease pathogenesis\u0026nbsp;\u003csup\u003e107\u003c/sup\u003e. Activated STING triggers membrane permeabilization and thus lysosomal cell death. cGAS\u0026ndash;STING\u0026ndash;lysosomal cell death combined with NLRP3 ameliorates the pathology of inflammatory conditions through cytosolic DNA sensing\u0026nbsp;\u003csup\u003e94\u003c/sup\u003e (\u003cstrong\u003eFig. 5\u003c/strong\u003e).\u0026nbsp;The SARS-CoV-2 ORF3a can interact with STING. It selectively blocks cGAS\u0026ndash;STING-induced autophagy by disrupting the STING-light chain 3 (LC3) interaction\u0026nbsp;\u003csup\u003e108\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe pathway induces microglial activation to resolve inflammation in the brain. However, excessive engagement can lead to neuroinflammation and neurodegeneration\u0026nbsp;\u003csup\u003e109\u003c/sup\u003e. cGAS\u0026ndash;STING signaling is strongly related to the pathogenesis of\u0026nbsp;neuroinflammation-driven disease progression\u0026nbsp;\u003csup\u003e110\u003c/sup\u003e. A vast array of germline-encoded innate immune receptors, commonly known as PRRs, facilitate innate immune recognition. Due to cellular senescence, autoimmune disorders, and mitotic stress in cancers, cytosolic DNA levels\u0026nbsp;increase. These events lead to the activation of cGAS\u0026ndash;STING and the exacerbation of pathological courses\u0026nbsp;\u003csup\u003e110\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e6.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eSpike protein pathway\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGlycoproteins are required for viral entry and fusion.\u0026nbsp;The SP is a trimeric glycoprotein encoded by ORF2 in the viral genome. The membrane-distal S1 subunit and proximal S2 subunit in the virus envelope form homotrimers\u0026nbsp;\u003csup\u003e111\u003c/sup\u003e. Glycoproteins derived from SARS-CoV-1, SACR-Co-V-2, human cytomegalovirus, and hepatitis C virus potentially trigger NLRP3 inflammasome activation and pyroptosis in THP-1 macrophages\u0026nbsp;\u003csup\u003e112\u003c/sup\u003e \u003csup\u003e113\u003c/sup\u003e. SP binding to ACE2 induces NF-\u0026kappa;B activation and inflammation via ACE2 in endothelial cells\u0026nbsp;\u003csup\u003e114\u003c/sup\u003e. The furin cleavage product of SP uses the vascular endothelial growth factor A (VEGF-A) binding site on NRP-1 as an entry point\u0026nbsp;\u003csup\u003e115\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe SARS-CoV-2 SP S1 subunit activated the NF-\u0026kappa;B and c-JNK signaling pathways. Furthermore, SP interacts with and activates TLR4\u0026nbsp;\u003csup\u003e25\u003c/sup\u003e \u003csup\u003e116\u003c/sup\u003e. SP\u0026nbsp;induces neuroinflammation in BV-2 microglia, a microglial cell line derived from C57BL/6 mice. Immunofluorescence microscopy revealed increased TLR4 expression in BV-2 microglia when stimulated with S1\u0026nbsp;\u003csup\u003e28\u003c/sup\u003e. After SARS-CoV-2 infection, the augmented immunogenicity of the SP results from macrophage reprogramming. SP-driven IL-1\u0026beta; secretion in macrophages requires nonspecific monocyte preactivation in vivo. Then, macrophages trigger NLRP3 inflammasome signaling\u0026nbsp;\u003csup\u003e117\u003c/sup\u003e. The SP drives inflammasome activation in macrophages isolated from convalescent COVID-19 patients, correlating with distinct epigenetic and gene expression signatures\u0026nbsp;\u003csup\u003e117\u003c/sup\u003e. The SP is a PAMP that requires macrophage preactivation for NLRP3 inflammasome\u0026nbsp;formation, and vigorous SP-driven inflammasome activity releases\u0026nbsp;IL-1\u0026beta;\u0026nbsp;in the convalescent macrophages of COVID-19 patients\u0026nbsp;\u003csup\u003e117\u003c/sup\u003e. However, it is not released in macrophages from healthy SARS-CoV-2-naive patients. SARS-CoV-2 infection causes profound and long-lived reprogramming of macrophages. This results in augmented immunogenicity of the SARS-CoV-2 SP, an effective vaccine antigen, which promotes potent adaptive and innate immune signaling\u0026nbsp;\u003csup\u003e117\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eSARS-CoV-2 infection can lead to syncytium formation within cells. The syncytia express ACE2 and SP, which produce approximately four micronuclei per syncytium. Remarkably, these micronuclei are highly expressed during the DNA damage response or during cGAS\u0026ndash;STING signaling, which is associated with cellular devastation and poor immune reactions\u0026nbsp;\u003csup\u003e118\u003c/sup\u003e \u003csup\u003e119\u003c/sup\u003e. Pathogenic platelet factor 4 (PF4)-dependent syndrome can occur after ChAdOx1 nCoV-19 vaccination\u0026nbsp;\u003csup\u003e120\u003c/sup\u003e. Various side effects caused by the vaccine\u0026rsquo;s SP appear in a real-time setting. The SP has a unique pathological mechanism: there are strange similarities with amyloid disease-associated blood coagulation and fibrinolytic disturbances together with neurologic and cardiac problems. The protease neutrophil elastase (NE) efficiently cleaves SP, exposes amyloidogenic segments, and accumulates the most amyloidogenic synthetic spike peptide, but full-length folded SP does not form amyloid fibrils\u0026nbsp;\u003csup\u003e121\u003c/sup\u003e \u003csup\u003e122\u003c/sup\u003e. SARS-CoV-2 SP vaccination establishes long-lived SP\u0026ndash;specific plasma cell reservoirs in the bone marrow of nonhuman primates\u0026nbsp;\u003csup\u003e123\u003c/sup\u003e. The SP might have induced immune reactions in humans.\u003c/p\u003e\n\u003cp\u003eLipid nanoparticles of the formulated nucleoside-modified mRNAs of SPs are stabilized in their prefusion conformation. They induce an immune reaction involving IL-2\u003csup\u003e+\u003c/sup\u003e CD8\u003csup\u003e+\u003c/sup\u003e and CD4\u003csup\u003e+\u003c/sup\u003e T helper type 1 cells or IFN\u0026gamma;+ cells\u0026nbsp;\u003csup\u003e124\u003c/sup\u003e. Lipid nanoparticles encode the prefusion conformation of SP. General adverse reactions include pain, swelling, redness, muscle pain, headache, fever, and chills after vaccination. Adverse events of special interest (AESI) included anaphylaxis, life-threatening disease, permanent disability/sequelae, and death. The overall seroprevalence of Korean anti-SARS-CoV-2 was very low on September 6, 2021, but the incidence of AESI was very high, as was the case in England during the pandemic. We compared AESI after vaccination in England and South Korea\u0026nbsp;\u003cstrong\u003e(Fig. 6).\u003c/strong\u003e These findings suggested that AESI might originate from immune reactions induced by lipid nanoparticles, including the SARS-CoV-2 SP, in mRNA vaccines\u0026nbsp;\u003csup\u003e12\u003c/sup\u003e \u003csup\u003e117\u003c/sup\u003e \u003csup\u003e123\u003c/sup\u003e \u003csup\u003e124\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eLike other RNA viruses, SARS-CoV-2 undergoes genetic evolution and develops mutations over time, resulting in the emergence of multiple variants that may have different characteristics than their ancestral strains\u0026nbsp;\u003csup\u003e125\u003c/sup\u003e \u003csup\u003e126\u003c/sup\u003e. The wild-type/Wuhan variant S1 is highly proinflammatory in zebrafish, but the\u0026nbsp;SP of the SARS-CoV-2 variants of interest shows differential proinflammatory effects\u0026nbsp;\u003csup\u003e127\u003c/sup\u003e. Moreover, the SP signals through TLR2 and activates NLRP3 in human macrophages from convalescent patients with COVID-19 but not from healthy SARS-CoV-2\u0026ndash;na\u0026iuml;ve individuals\u0026nbsp;\u003csup\u003e117\u003c/sup\u003e. SP can prime the NLRP3 inflammasome and enhance caspase-1 activity through NF-\u0026kappa;B signaling. S1 interacts with amyloid-beta, prion protein,\u0026nbsp;\u0026alpha;-Syn, and tau, presumably through heparin-binding domains, to form homopolymers or heteropolymers resembling amyloid fibrils in the neurodegenerative process of misfolded protein disorders in the brain and increases the protein level of p38 MAPK in BV-2 microglia. S1 also binds to transactive response DNA-binding protein 43 (TDP-43) and RNA-binding motifs (RRMs); TDP-43 RRM is involved in amyotrophic lateral sclerosis (ALS) and AD. The interaction of\u0026nbsp;the SP with the prion protein is more robust than that with amyloid-beta, tau, or\u0026nbsp;\u0026alpha;-Syn\u0026nbsp;\u003csup\u003e28\u003c/sup\u003e \u003csup\u003e98\u003c/sup\u003e \u003csup\u003e128\u003c/sup\u003e. The hyperinflammatory state of COVID-19 triggers CNS neuroinflammation by activating astrocytes and microglia. This condition could facilitate prion-like pathology\u0026nbsp;\u003csup\u003e129\u003c/sup\u003e. Like other prion proteins, the SP contains several prionogenic domains. SP triggers a neurodegenerative condition known as prion-disease-like pathology\u0026nbsp;\u003csup\u003e130\u003c/sup\u003e.\u0026nbsp;SP can catalyze the aggregation of aggregation-prone proteins in the brain, and spike-derived peptides can act as functional amyloids. Cross-reactive antibodies can originate from many reported complications, such as the worsening of demyelinating diseases, Guillain\u0026ndash;Barr\u0026eacute; syndrome, immune thrombotic thrombocytopenia, and stroke\u0026nbsp;\u003csup\u003e131\u003c/sup\u003e. As a result, rare hypersensitivity reactions to mRNA-based SARS-CoV-2 vaccines develop, such as anaphylaxis, chest pain, chills, flushing, hypertension, and tachycardia\u0026nbsp;\u003csup\u003e12\u003c/sup\u003e \u003csup\u003e132\u003c/sup\u003e.\u0026nbsp;In addition, two distinct self-limiting syndromes, myocarditis and pericarditis, occur in only one patient after COVID-19 vaccination. Specifically, myocarditis develops rapidly in younger patients. It occurred mainly after the second vaccination. However, pericarditis, which occurs after receiving mRNA vaccines, affects older people after the first or second vaccination\u0026nbsp;\u003csup\u003e133\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7. Immunological memory engram pathway\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA single or double layer of invaginated pia forms an interstitial fluid-filled space in the perivascular space in the brain. The space represents an extension of the extracellular fluid space around the intracranial vessels that descend into the brain parenchyma\u0026nbsp;\u003csup\u003e134\u003c/sup\u003e. Human sensory stimuli and abnormal muscular sensations affect breathing via the cerebral cortex and hypothalamus\u003csup\u003e135\u003c/sup\u003e \u003csup\u003e136\u003c/sup\u003e. The substrate of information is stored in cells termed engram cells\u0026nbsp;\u003csup\u003e137\u003c/sup\u003e. The brain can trigger immune reactions in patients with COVID-19. The subsequent reactivation of the engram stimulates memory retrieval of immune-related information in the insular cortex\u0026nbsp;\u003csup\u003e138\u003c/sup\u003e. Chemogenetic reactivation reflects the inflammatory conditions described in the insular cortex\u0026nbsp;\u003csup\u003e139\u003c/sup\u003e. The immunological memory engram pathway\u0026nbsp;can restore the initial disease state\u0026nbsp;during COVID-19 pathogenesis\u0026nbsp;\u003csup\u003e140\u003c/sup\u003e.\u0026nbsp;SARS-CoV-2 infection during the fetal period may alter the normal functioning of the brain region where memory engrams are generated and affect neuronal progenitor cells\u0026nbsp;\u003csup\u003e141\u003c/sup\u003e. The massive infection rate in young people leads to the possibility of an increase in the incidence of congenital infections and originating cognitive alterations in terms of new variants; consequently, neuronal circuit anomalies may indicate vulnerability to mental problems throughout life\u0026nbsp;\u003csup\u003e141\u003c/sup\u003e \u003csup\u003e142\u003c/sup\u003e \u003csup\u003e143\u003c/sup\u003e \u003cstrong\u003e(Fig. 7)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eSARS-CoV-2 may disrupt BBB dysfunction by damaging the choroid plexus epithelium through cytokine, chemokine, and adhesion molecule storms\u0026nbsp;\u003csup\u003e144\u003c/sup\u003e \u003csup\u003e145\u003c/sup\u003e. The neuropathology of COVID-19 brains was significantly greater than the microgliosis and T-cell infiltration in COVID-19-free patients. Altered brain T-cell-microglia interactions are linked to profound neuroinflammation\u0026nbsp;\u003csup\u003e146\u003c/sup\u003e. This might trigger inflammasomes and pyroptosis in the CNS. Brainstem involvement could explain sudden deaths by respiratory failure\u0026nbsp;\u003csup\u003e147\u003c/sup\u003e \u003csup\u003e148\u003c/sup\u003e \u003csup\u003e149\u003c/sup\u003e. COVID-19 is characterized by the rapid development of acute lung injury, ARDS, death due to dysregulated cytokine release, disseminated intravascular coagulation (DIC), multisystem failure, and pneumonia. However, COVID-19 causes unique type L or H phenotype lung injury and requires different ventilatory approaches, depending on the underlying physiology\u0026nbsp;\u003csup\u003e54\u003c/sup\u003e. Often, preexisting neurological disease may become clinically evident or worsen to immune suppression or modulation\u0026nbsp;\u003csup\u003e150\u003c/sup\u003e. ACE2 expression in the lungs is modest compared to that in other organs, such as the heart, kidneys, and small intestines. However, TLR4 is expressed intracellularly on the whole body\u0026apos;s dendritic, epithelial, and endothelial cells\u0026nbsp;\u003csup\u003e151\u003c/sup\u003e \u003csup\u003e152\u003c/sup\u003e.\u0026nbsp;Conventional dendritic cells are highly specialized antigen-presenting cells that are key initiators and regulators of T-cell-mediated immunity, and their absence in a murine line lacking conventional dendritic cells results in consequent impaired CD8+ T-cell responses and subsequently in a significant increase in the SARS-CoV-2 viral load in the lungs\u0026nbsp;\u003csup\u003e153\u003c/sup\u003e. Microglia and astrocytes participate in immune-to-brain communication during immune activation. Glia, microglia, and astrocytes propagate inflammatory signals and influence physiological responses in the body\u0026nbsp;\u003csup\u003e154\u003c/sup\u003e.\u0026nbsp;Janus kinase (JAK)1-dependent type 2 cytokines promote atopic dermatitis and asthma, and human JAK1 gain-of function variant (\u003cem\u003eJAK1\u003c/em\u003e\u003csup\u003eGoF\u003c/sup\u003e) leads to the development of spotanous atopic dermatitis and staggering of JAK1 in the vagus nerve to induce lung inflammation. Subsequent genetic expression suppresses group 2 ILC function and allergic airway inflammation.\u0026nbsp;\u003csup\u003e155\u003c/sup\u003e ACE2 is localized to the cytoplasm, and its expression appears to be highly regulated by other renin-angiotensin system components. In transgenic mouse brains, ACE2 is present in the cytoplasm of neuronal cell bodies but not in glial cells. ACE2 in transgenic mice was significantly increased in an area lacking the blood‒brain barrier and sensitive to blood-borne angiotensin II\u0026nbsp;\u003csup\u003e156\u003c/sup\u003e. Activating the peripheral immune system via the immunologically coordinated engram pathway elicits exaggerated COVID-19 symptoms. This immunological memory engram pathway is activated during COVID-19 pathogenesis\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e8. Excess\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eacetylcholine pathway activity\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ein dementia patients with anti-Alzheimer\u0026rsquo;s disease\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSARS-CoV-2 was shown to trigger neuroinflammation in the olfactory mucosa in AD patients\u0026nbsp;\u003csup\u003e157\u003c/sup\u003e, and an analgesic agent against neuroinflammation was shown to prevent and treat AD exacerbation\u0026nbsp;\u003csup\u003e158\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e8.1 More details on rationale\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe observed the effects of excess acetylcholine in combination with the drug Alzheimer\u0026rsquo;s disease (AD) (AAD) on the sustained viral RNA interferon response. VRDs cause lung inflammation and inflammatory cytokine production. Participants were randomized to VRDs after prescribing dapsone as a standard treatment or AADs as AD symptom treatments from 2005 to 2019 in an\u0026nbsp;RCT. The incidence of endemic diseases on Sorok Island, South Korea, sharply increased from 2008 to 2009; that of\u0026nbsp;chronic obstructive pulmonary disease (COPD)\u0026nbsp;increased rapidly in 2012 and 2013; that of acute bronchitis increased from 2012 to 2014; and that of pneumonia increased in 2013 compared to earlier years.\u0026nbsp;The equation for the use of dapsone in combination with acetylation as a preventive treatment for VRDs and excess ACh in AADs (AA equation) was strongly negatively correlated with the incidence of bronchitis and COPD. Excess ACh produced by AADs exacerbates bronchitis and COPD\u0026nbsp;\u003csup\u003e159\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe muscarinic (M) and nicotinic ACh receptors play life-threatening roles in regulating immune function. Viral\u0026nbsp;infection and interferon treatment cause the release of IFN-\u0026gamma;, decrease M2 receptor gene expression at parasympathetic nerve endings, and ultimately inhibit M2 receptor gene expression\u0026nbsp;\u003csup\u003e59\u003c/sup\u003e \u003csup\u003e61\u003c/sup\u003e.\u0026nbsp;COVID-19 is regarded as a hyperinflammatory disease characterized by cytokine release by harmful immune cells. However, the plasma concentrations of these viruses are close to those provoked by classical viral respiratory infections (VRDs), such as influenza\u0026nbsp;\u003csup\u003e160\u003c/sup\u003e \u003csup\u003e161\u003c/sup\u003e.\u0026nbsp;VRDs and IFN-1 induce the loss of inhibitory M2 receptor function and gene expression in cultured airway parasympathetic neurons. Moreover, the excess ACh produced by AADs appears to inhibit the production of the ACh receptor, which prevents virus invasion\u0026nbsp;\u003csup\u003e159\u003c/sup\u003e \u003cstrong\u003e(Fig. 8)\u003c/strong\u003e.\u0026nbsp;The cohort study indicated another exacerbating factor related to the viral diseases on Sorok Island.\u003c/p\u003e\n\u003cp\u003e8.2 Supporting evidences\u003c/p\u003e\n\u003cp\u003eAs of April 17, 2022, there were 55,841 cases of COVID-19 reinfection in South Korea, for an incidence rate of 0.35%. Ninety days after the initial diagnosis, there were 53,301 cases of reinfection, which accounted for 95.5% of the total cases. A total of 99.0% of reinfection cases occurred during the period when the omicorn virus was dominant. There were 72 patients with exacerbated COVID-19; 70 (97.2%) patients had exacerbated disease after 50 years of age, and 52 (100%) patients died after 50 years of age\u0026nbsp;\u003csup\u003e162\u003c/sup\u003e. Sixty-seven of the 72 cases (93.1%) occurred in nursing hospitals and homes. Patients in nursing hospitals and homes take the following AD drugs: donepezil, choline alfoscerate, rivastigmine, galantamine, and memantine\u0026nbsp;\u003csup\u003e163\u003c/sup\u003e. We compared higher risk\u0026nbsp;subjects who had elapsed since receiving the third vaccination because the fourth COVID-19 vaccine dose was first released from February 16 to April 30, 2022. We analyzed the data of 1,509,970 participants in the high-risk groups, namely, residents of patients in elderly care hospitals and facilities (E1) and immunocompromised individuals (E2). Standardizing per 100,000, infection after the third vaccine was 71.7% (E1) and 28.3%, and severity was 89.4% (E1) and 10.6% (E2), death was 92.0% (E1) and 8.0% (E2), and infection after the fourth vaccine was 74.2% (E1) and 25.8% (E2). The severity of infection was 91.5% (E1) and 8.5% (E2), and the mortality rates were 93.8% (E1) and 6.2% (E2)\u0026nbsp;\u003csup\u003e164\u003c/sup\u003e.\u0026nbsp;One major factor is that, compared with E2, E1 has excess ACh, which increases susceptibility to infection and exacerbates severity and mortality.\u0026nbsp;Excess\u0026nbsp;ACh appears to inhibit ACh receptors to promote IFN production during viral invasion\u0026nbsp;\u003csup\u003e159\u003c/sup\u003e \u003csup\u003e165\u003c/sup\u003e. Excess ACh related to AD and related dementias is an underlying or contributing cause of excess mortality in nursing homes, long-term care settings, homes, and medical facilities\u0026nbsp;\u003csup\u003e166\u003c/sup\u003e \u003csup\u003e167\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e8.3 Limitations\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA wide variety of factors simultaneously act as aggravating factors. Increased levels of oxidative stress, desensitized inflammation, and immune responses, and alterations to genes associated with olfaction were shown in the transcriptomic signatures of olfactory mucosa cells at the air-liquid interface from individuals with AD\u0026nbsp;\u003csup\u003e157\u003c/sup\u003e. Gut microbiota imbalances can trigger several immune disorders through the activity of T cells, both near and distant from the site of induction\u0026nbsp;\u003csup\u003e168\u003c/sup\u003e. The gut microbiota drives systemic antiviral immunity via IFN-I priming, and microbiota-driven IFN-I priming involves the cGAS\u0026ndash;STING axis\u0026nbsp;\u003csup\u003e169\u003c/sup\u003e. Nevertheless, the nucleotide-binding oligomerization domain containing 2 (NOD2) in the hypothalamus recognizes neuropeptides and fragments of bacterial cell walls, which change temperature regulation and feeding behavior in mice, particularly older female mice\u0026nbsp;\u003csup\u003e170\u003c/sup\u003e. These findings explain the multidimensional roles of human IFN in regulating senescence, autophagy, apoptosis, antitumor effects, and cell metabolism\u0026nbsp;\u003csup\u003e171\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cstrong\u003ePerspective on implications and limitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eILC3s are essential for host defense against infection and tissue homeostasis. ILC3s depend on the transcription factor retinoic acid-related orphan receptor-gamma \u0026gamma;t (ROR\u0026gamma;t). It plays a role in angiogenesis, initiating ectopic pulmonary lymphoid aggregates\u0026nbsp;\u003csup\u003e48\u003c/sup\u003e. In addition, ILC3s harboring NRP1 (NRP1\u003csup\u003e+\u003c/sup\u003e ILC3s) are found in ectopic lymphoid aggregates in patients with chronic lung disease. NRP1\u003csup\u003e+\u003c/sup\u003e ILC3s also potentially contribute to inflammation and vascularization\u0026nbsp;\u003csup\u003e46\u003c/sup\u003e. NRP1\u003csup\u003e+\u003c/sup\u003e ILC3s are present in the lymphoid tissues and lung tissues of smokers and\u0026nbsp;COPD\u0026nbsp;patients. NRP1\u003csup\u003e+\u003c/sup\u003e ILC3s produce more cytokines than ILC3s without NRP1 (NRP1\u003csup\u003e-\u003c/sup\u003e ILC3s)\u0026nbsp;\u003csup\u003e48\u003c/sup\u003e.\u0026nbsp;The gut microbiota with acetate modulates ILC3 immunity\u0026nbsp;\u003csup\u003e172\u003c/sup\u003e.\u0026nbsp;The gut microbiota drives systemic antiviral immunity.\u0026nbsp;T and B cells in the mucosa play pivotal roles in maintaining immune homeostasis by suppressing responses to harmless antigens and ensuring the integrity of the barrier functions of the gut mucosa\u0026nbsp;\u003csup\u003e168\u003c/sup\u003e. The microbiota mediates systemic IFN-I priming via DNA-containing membrane vesicles\u0026nbsp;\u003csup\u003e169\u003c/sup\u003e.\u0026nbsp;The prevention of microbiota-driven IFN-I involves the cDNA sensor cGAS\u0026ndash;STING axis\u0026nbsp;\u003csup\u003e169\u003c/sup\u003e.The microbiota influences position-specific phenotypes and functions\u0026nbsp;\u003csup\u003e171\u003c/sup\u003e.\u0026nbsp;Moreover, ACh excess by AADs might inhibit ACh receptors for IFN production and exacerbate COVID-19\u0026nbsp;\u003csup\u003e159\u003c/sup\u003e \u003csup\u003e162\u003c/sup\u003e \u003csup\u003e164\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCOVID-19 induces an immune response in CD8+ T cells, in which feedback activates the NLRP3 inflammasome in an antigen-dependent manner to promote IL-1\u0026beta; maturation on APCs\u0026nbsp;\u003csup\u003e173\u003c/sup\u003e \u003csup\u003e174\u003c/sup\u003e \u003csup\u003e175\u003c/sup\u003e. CD8+ T cells might originate from T-cell activation caused by HLA polymorphisms\u0026nbsp;\u003csup\u003e176\u003c/sup\u003e. T cells from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQ13:01KLIANQF\u0026nbsp;\u003csup\u003e177\u003c/sup\u003e. At least 20% of individuals with an HLA-B*15:01 status are asymptomatic\u0026nbsp;\u003csup\u003e178\u003c/sup\u003e \u003csup\u003e179\u003c/sup\u003e. The weak binding affinity of HLA polymorphisms might contribute to SARS-CoV-2 Omicron\u0026rsquo;s immune evasion\u0026nbsp;\u003csup\u003e180\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn viral diseases, excessive production or decreased production of IFN may be an important factor in ultimately worsening pathology. However, in the eight studies in this study, too many complex and diverse pathways are involved in IFN, making it difficult to find treatments that can effectively and efficiently manage it.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAn outlook on important questions remaining and directions for future investigations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eActivating cytokines or PAMPs leads to the transcriptional upregulation of canonical and noncanonical inflammasome components\u0026nbsp;\u003csup\u003e181\u003c/sup\u003e. IFN-I-activated microglia and other brain cells arise and expand in amyloidosis, and IFN-I signaling promotes plaque accumulation in neural cells\u0026nbsp;\u003csup\u003e182\u003c/sup\u003e. Manry et al. reported that circulating autoantibodies neutralizing IFN-\u0026alpha;, IFN-\u0026omega;, and IFN-\u0026beta; increased fatality in 1,261 patients who died and 34,159 individuals from the general population\u0026nbsp;\u003csup\u003e183\u003c/sup\u003e.\u0026nbsp;Among the COVID-19-positive veterans who were in the Armed Forces, a previous aspirin prescription was clinically significantly associated with a decrease in overall mortality at 14 days (OR, 0.38) and 30 days (OR, 0.38)\u0026nbsp;\u003csup\u003e184\u003c/sup\u003e.\u0026nbsp;Sera from patients with COVID-19 have elevated levels of cell-free DNA, myeloperoxidase (MPO)-DNA complexes, and citrullinated histone H3. The levels of cell-free DNA and MPO-DNA were high in hospitalized patients receiving mechanical ventilation or breathing room air\u0026nbsp;\u003csup\u003e185\u003c/sup\u003e.\u0026nbsp;Dexamethasone administered at a cumulative dose between 60\u0026thinsp;and 150\u0026thinsp;mg was associated with reduced mortality only in patients requiring respiratory support\u0026nbsp;\u003csup\u003e186\u003c/sup\u003e. In COVID-19 and other ARDS cases, a high neutrophil-to-lymphocyte ratio (NLR) is associated with increased myeloid-derived suppressor cells (MDSCs)\u0026nbsp;\u003csup\u003e187\u003c/sup\u003e \u003csup\u003e188\u003c/sup\u003e. An elevated NLR and typical bone marrow emergency granulopoiesis in COVID-19 patients are related to increased MDSC numbers\u0026nbsp;\u003csup\u003e189\u003c/sup\u003e \u003csup\u003e190\u003c/sup\u003e. MDSCs increase immunosuppressive activity and are critical during severe COVID-19\u0026nbsp;\u003csup\u003e191\u003c/sup\u003e. According to an RCT, the incidence of VRDs associated with dapsone was lower than that associated with VRDs without dapsone\u0026nbsp;\u003csup\u003e159\u003c/sup\u003e.\u0026nbsp;Dapsone treatment was associated with a lower NLR in the ICU\u0026nbsp;\u003csup\u003e57\u003c/sup\u003e \u003csup\u003e158\u003c/sup\u003e \u003csup\u003e192\u003c/sup\u003e \u003csup\u003e193\u003c/sup\u003e. The HLA polymorphisms might be associated with Omicron evasion\u0026nbsp;\u003csup\u003e180\u003c/sup\u003e and\u0026nbsp;dapsone hypersensitivity is susceptible to the expression of HLA-B*13:01\u0026nbsp;\u003csup\u003e194\u003c/sup\u003e \u003csup\u003e195\u003c/sup\u003e. It relates the treatment asymptomatic with an HLA-B*15:01 status\u0026nbsp;\u003csup\u003e178\u003c/sup\u003e \u003csup\u003e179\u003c/sup\u003e. Anticatalysis might be used as an asymptomatic treatment for COVID-19, as in asymptomatic individuals carrying HLA-B*15:01. We explored immune strategies for preventing COVID-19-related exacerbation of pathophysiology (\u003cstrong\u003eTable 2)\u003c/strong\u003e.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCOVID-19 is exacerbated via seven pathways. COVID-19 is exacerbated by ACE2-TLR4, NRP1, SAMHD1, inflammasome, cGAS\u0026ndash;STING, SP, and immunologic engram. Moreover, excess ACh during SARS-CoV-2 variant invasion might inhibit ACh receptors to promote IFN production, but the excess ACh pathway requires further validation. The first-line anti-catalytic triad needs to prevent and block pathological processes, mutations, and deterioration.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe National Agency approved this study for the Management of Life-sustaining Treatment, which certified that life-sustaining treatments were managed properly (Korea National Institute for Bioethics Policy (KoNIBP) approval number P01-202007-22-006).\u003c/p\u003e\n\u003cp\u003eIn 2021, as external activities were difficult during the pandemic era, we analyzed SCI journals according to L. Wittgenstein\u0026apos;s Tractatus Logico-Philosophicus\u0026nbsp;\u003csup\u003e196\u003c/sup\u003e. We investigated and pictured the SARS-CoV-2 penetration route with seven deductions. When these are called basic propositions, the proposition must be the truth function of the basic proposition. If If it is a tautology of (p, q) (T T T T), then p is p (p ⸧ p) and q is q (q ⸧ q). An easy way to prove these is to observe whether the experimental results found are repeated over a period of 1-2 years.\u003c/p\u003e\n\u003cp\u003eInclusion criteria. Through information search, key words were connected based on the research results. The order is as follows: 1) the angiotensin-converting enzyme 2 (ACE2) and Toll-like receptor (TLR), 2) the neuropilin (NRP), 3) the sterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein 1 (SAMHD1) tetramerization, 4) the inflammasome activation, 5) the cytosolic DNA sensor cyclic-AMP synthase (cGAS)/stimulator of interferon genes (STING) (cGAS\u0026ndash;STING) signaling, 6) the spike protein with vaccines, and 7) the immunological memory engram.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExclusion criteria: If experimental data was not repeated\u0026nbsp;SCI journals, those were excluded.\u003c/p\u003e\n\u003cp\u003eWe published a preprint (related material) on January 14, 2022.\u003c/p\u003e\n\u003cp\u003ePreprint: Lee, J. (2022, January 14). Pathology and Anticatalysis treatment of exacerbated COVID-19. https://doi.org/10.31219/osf.io/t9wjz (version 1. 01/14/2022 09:27:40) (Supplement 2)\u003c/p\u003e\n\u003cp\u003eThe preprint was exposed to Views: 617/Downloads: 274. This preprint has been updated to the final version 18 (September 30, 2023) for the support of related information. This study is not a simple retrieval of systemic reviews but rather a prediction of seven pathways using picture theory for the real world during the pandemic\u0026nbsp;\u003csup\u003e196\u003c/sup\u003e. We analyzed the final results on December 3, 2023.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn addition, we conducted the data analysis to find new paths. According to the Korea Drug Code of Medicine,\u0026nbsp;the ADs for symptomatic relief are donepezil hydrochloride, rivastigmine, galantamine, and memantine. The\u0026nbsp;ADs used for psychological symptoms were haloperidol, risperidone, quetiapine, olanzapine, aripiprazole, oxcarbazepine, fluvoxamine, escitalopram, trazodone, sertraline, escitalopram, and fluoxetine. The cumulative number of confirmed cases of coronavirus disease 2019 (COVID-19) was 16,130,920 from January 2020 to April 16, 2022. Based on the status of confirmed cases up to April 16, 2022, in the COVID-19 information management system of the Korea Centers for Disease Control and Prevention, a survey of total cases of COVID-19 reinfection was conducted\u0026nbsp;\u003csup\u003e162\u003c/sup\u003e \u003csup\u003e164\u003c/sup\u003e. Per the Information Disclosure Act, we obtained relevant information of registration number 9318128 from the Korea Disease Control and Prevention Agency (Supplement 3). A reinfection was defined as a case in which a positive polymerase chain reaction (PCR) or professional rapid antigen test (RAT) result was confirmed 45 days after the first confirmation, regardless of the presence or absence of symptoms.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe National Agency approved this study for the Management of Life-sustaining Treatment, which certified that life-sustaining treatments were managed properly (Korea National Institute for Bioethics Policy (KoNIBP) approval number P01-202007-22-006).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors affirm that the human research participants provided informed consent for the publication of the manuscript results.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors listed have made substantial, direct, and intellectual contributions to the work and approved it for publication.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJ.L. designed this study and the methodology and wrote this manuscript; S.C. and K.L. introduced dexamethasone use at O2 2L/min states and proved its safety and effectiveness; C.S., E.L.A. and M.D.C. reviewed the manuscript; M.D.C. examined dexamethasone use.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo data associated with the manuscript\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eA549 cell\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eA549 cells are adenocarcinomic human alveolar basal epithelial cells, and constitute a cell line.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eACE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eAngiotensin-converting enzyme\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eAlzheimer\u0026rsquo;s disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eAESI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eAdverse events of special interest\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eAIDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eAcquired Immune Deficiency Syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eAGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eAicardi\u0026ndash;Gouti\u0026egrave;res syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eAIM2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eAbsent in melanoma 2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eALI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eAir\u0026ndash;liquid interface\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eALP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eAlkaline phosphatase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026alpha;-Syn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026alpha;-synuclein\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eAMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eAcute myocardial infarction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eAMI I/R injury\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eAMI ischemia\u0026ndash;reperfusion injury\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eAMPA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026alpha;-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eAPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eAntigen-presenting cells\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eARDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eAcute respiratory distress syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eASC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eApoptosis-associated speck-like protein containing a CARD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eATF4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eActivated parkin via protein kinase RNA-like endoplasmic reticulum kinase-activating transcription factor 4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eBBB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eBlood‒brain barrier\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eBDNF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eBrain-derived neurotrophic factor\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eBiPAP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eBilevel positive airway pressure\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eBV-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eA type of microglial cell derived from C57/BL6 mice\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCAPS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eCryopyrin-associated periodic syndromes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCARD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eCaspase activation and recruitment domain\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCCNE2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eEssential for the control of the cell cycle at the late G1 and early S phases; belongs to the cyclin family\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCCR5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eC\u0026ndash;C motif chemokine receptor 5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eClonal hematopoiesis, hematopoietic stem and progenitor cells\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCDK1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eCyclin-dependent kinase 1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eConfidence interval\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCK-MB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eCreatine kinase-MB fraction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCOPD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eChronic obstructive pulmonary disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCOX-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eCyclooxygenase 1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCRP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eC-reactive protein\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eCytokine release syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCtIP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eC-terminal binding protein 1 (CtBP1) interacting protein\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCyclin-A2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eA protein that in humans is encoded by the CCNA2 gene. It is one of the two types of cyclin A: cyclin A1 is expressed during meiosis and embryogenesis while cyclin A2 is expressed in the mitotic division of somatic cells.[\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCyclin D1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eA protein required for progression through the G1 phase of the cell cycle\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCyclin D3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eA cofactor of retinoic acid receptors, modulating their activity in the presence of cellular retinoic acid-binding protein II\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCyclin E2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eCyclin E2 is a protein that in humans is encoded by the CCNE2 gene\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCyclin-G1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eA protein that in humans is encoded by the CCNG1 gene\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eCXCR-4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eC-X-C chemokine receptor type 4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eDDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003e4,4\u0026prime;-Diaminodiphenyl sulfone (dapsone)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eDPP4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eDipeptidyl peptidase-4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eDIC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eDisseminated intravascular coagulation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eECG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eElectrocardiogram\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eER\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eEndoplasmic reticulum\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003ecGAMP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003e2\u0026prime;,3\u0026prime;-cyclic GMP-AMT\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003ecGAS\u0026ndash;STING\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003ecytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eG6PDH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eGlucose-6-phosphate dehydrogenase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eHAART\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eHighly active antiretroviral therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eHIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eHuman Immunodeficiency Virus\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eHLA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eHuman leukocyte antigen\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eHLA-DRB1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eMajor histocompatibility complex, class II, DR beta 1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eHSPC\u003c/p\u003e\n \u003cp\u003eICU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003ehematopoietic stem/progenitor cell\u003c/p\u003e\n \u003cp\u003eIntensive care unit\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eIFN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eInterferon\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eIFNAR2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eInterferon-alpha and beta receptor subunit 2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eIL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eInterleukin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eIL-1\u0026beta;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eInterleukin-1 beta\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eIMV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eintensive mechanical ventilation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eIRF3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eInterferon regulatory factor 3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eJNK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eJun N-terminal kinases\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eLDH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eLactate dehydrogenase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eLDL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eLow-density lipoprotein\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eLL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eLepromatous leprosy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eLPS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eLipopolysaccharide\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eLTP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eLong-term potentiation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eM receptor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eMuscarinic receptor\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eMADDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eMonoacetyldapsone\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eMAPK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eMitogen-activated protein kinase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eMCI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eMild cognitive impairment\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eMDIG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eMineral dust-induced gene\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eMHC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eMajor histocompatibility complex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eMIS-C/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eMultisystem inflammation syndrome in children and adults\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eMPO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eMyeloperoxidase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eN receptor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eNicotinic receptor\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eNOD2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eNucleotide-binding oligomerization domain containing 2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eN protein\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eNucleocapsid protein\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eMDA5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003emelanoma differentiation-associated gene 5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003emRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eMessenger RNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003emtDNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eMitochondrial DNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eNACHT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eDomain conserved in NAIP, CIITA, HET-E, and TP1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eNFL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eNeurofilament light chain\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eNF-\u0026kappa;B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eNuclear factor kappa-light-chain-enhancer of activated B cells\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eNLRC4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eNLR Family CARD Domain Containing 4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eNLRP3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eNOD-, LRR-, and pyrin domain-containing protein 3\u003c/p\u003e\n \u003cp\u003eNLR family pyrin domain-containing 3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eNRP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eNeuropilin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003ePAI-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003ePlasminogen activator inhibitor-1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003ePAMPs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003ePathogen-associated molecular patterns\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003ePBMCs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eHuman peripheral blood mononuclear cells\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eParkinson\u0026rsquo;s disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003ePEDF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003ePigment epithelium-derived factor\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003ePEDFR/iPLA2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003ePEDF/calcium-independent phospholipase A2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003ePhosphomimetics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eAmino acid substitutions that mimic a phosphorylated protein.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003ePhospho-p65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eAnti-phospho-NFkB p65 (Ser536) monoclonal antibody (T.849.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003ePhospho-I\u0026kappa;B\u0026alpha;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003ePhospho-I\u0026kappa;B\u0026alpha; (Ser32/36) (5A5) mouse mAb #9246\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003ePRMT5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eProtein arginine methyltransferase 5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003ePTGS2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eProstaglandin synthase 2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003ePTM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eMultiple posttranslational modification\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eRIG-I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eRetinoic acid-inducible gene I\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eROS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eReactive oxygen species\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eSP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eSpike glycoprotein of SARS-CoV-2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eS1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eSARS-CoV-2 spike protein subunit 1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eSAMHD1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eSterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eSCLS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eSystemic capillary leak syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eRandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eSOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eSuperoxide dismutase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eTGF\u0026beta;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eTransforming growth factor-beta\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eTHP-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eA spontaneously immortalized monocyte-like cell line\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eTNF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eTumor necrosis factor\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eTLR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eToll-like receptor\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eTMPRSS2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eTransmembrane protease serine subtype 2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eTRIF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eTLR3-TIR-domain-containing adapter-inducing interferon-\u0026beta;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eTTS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eThrombosis with thrombocytopenia syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eTREX1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eTthree-prime repair exonuclease 1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eTYK2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eTyrosine kinase 2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eUCB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eUmbilical cord blood\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eVRD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eViral respiratory disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.151515151515152%\" valign=\"top\"\u003e\n \u003cp\u003eVSEL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"84.84848484848484%\" valign=\"top\"\u003e\n \u003cp\u003eVery small embryonic-like stem cell\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Tables ","content":"\u003cp style='margin:0in;text-align:justify;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTable 1 COVID-19 picture on the basis of the real world\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width:544.25pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 53.75pt;border: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 245.25pt;border-width: 1pt 1pt 1pt medium;border-style: solid solid solid none;border-color: windowtext windowtext windowtext currentcolor;border-image: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eThe 1st version 2022-01-14\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 245.25pt;border-width: 1pt 1pt 1pt medium;border-style: solid solid solid none;border-color: windowtext windowtext windowtext currentcolor;border-image: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eThe last in 2024-01-04\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 53.75pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122.6pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e*1\u003c/span\u003e\u003c/sup\u003e\u003c/strong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eOriginal 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5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e2020-2021\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122.65pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e2022-2024\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 53.75pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;height: 163.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e1. 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Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(26) (Kucia et al, 2021)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(27,28) (Choudhury \u0026amp; Mukherjee, 2020)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(29) (Olajide et al, 2021)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(30) (Rannikko et al, 2015)\u003csup\u003e\u0026nbsp;\u003cstrong\u003e*4\u003c/strong\u003e\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(31) (Conte, 2021)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(32) (Jurgens et al, 2012)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(33) (Tanaka et al, 2018)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(34) (Sparkman et al, 2019)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(35) (Muscat \u0026amp; Barrientos, 2021)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(36) (Boldrini et al, 2021)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(37,38) (Zeberg \u0026amp; P\u0026auml;\u0026auml;bo, 2020)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n 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Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e30\u003c/span\u003e\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Conte, 2021)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:16px;font-family: \"Times New Roman\",serif;'\u003e\u003csup\u003e198\u003c/sup\u003e\u003c/span\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Jurgens et al, 2012)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:16px;font-family: \"Times New Roman\",serif;'\u003e\u003csup\u003e199\u003c/sup\u003e\u003c/span\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Tanaka et al, 2018)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:16px;font-family: \"Times New Roman\",serif;'\u003e\u003csup\u003e200\u003c/sup\u003e\u003c/span\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Sparkman et al, 2019)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cs\u003e\u003cspan style='font-size:16px;font-family:\"Times New 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style='font-family:\"Times New Roman\",serif;'\u003e31\u003c/span\u003e\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Zeberg \u0026amp; P\u0026auml;\u0026auml;bo, 2020)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122.6pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;height: 163.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e11\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Devaux et al, 2020)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e13\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Kumar et al, 2021)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e15\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Chlamydas et al, 2021)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cem\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New 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style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122.65pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New 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style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122.6pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e32\u003c/span\u003e\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(Daly et al. 2020)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e33\u003c/span\u003e\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Cantuti-Castelvetri et al. 2020)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e34\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Hoffmann et al. 2020)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e35\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(Mollica, Rizzo, and Massari 2020)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e36\u003c/span\u003e\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New 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style='font-family:\"Times New Roman\",serif;'\u003e50\u003c/span\u003e\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Khan et al. 2021)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e51\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(Yong 2021)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e38\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(Group 2020)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e39\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Li et al. 2020)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e41\u003c/span\u003e\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Zeberg and P\u0026auml;\u0026auml;bo 2021)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e42\u003c/span\u003e\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(Zhang, Wadgaonkar, et al. 2021)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n 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2022)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e52\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Lucchese et al. 2022)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:justify;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e40\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Kerner and Quintana-Murci 2022)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e43\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Zhang et al, 2022)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e45\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Spits \u0026amp; Mj\u0026ouml;sberg, 2022)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e55\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Kawano et al, 2023)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e56\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Dangarembizi \u0026amp; Drummond, 2023)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino 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style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"text-decoration:none;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"text-decoration:none;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 53.75pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e3. 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style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e84\u003c/span\u003e\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Pan et al. 2021)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e91\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(Han et al. 2021)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e92\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(Rui et al. 2021)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e95\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Lee et al, 2020)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino 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style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e90\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(Han et al. 2022)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:justify;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e93\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp; (Deng et al. 2023)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp 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style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(67) (Fengjuan Li, 2021)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(68) (Ren et al, 2021)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(69) (Gaidt et al, 2017)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(70) (Aarreberg et al, 2019)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(71) (Bolton et al, 2021)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(72) (Hammond \u0026amp; Loghavi, 2021)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122.65pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:justify;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e104\u003c/span\u003e\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(de Oliveira Mann \u0026amp; Hopfner, 2021)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:justify;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e109\u003c/span\u003e\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Paul et al, 2021)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:justify;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New 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2021)\u003c/span\u003e\u003c/s\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:justify;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cs\u003e\u003cspan style='font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003csup\u003e207\u003c/sup\u003e\u003c/span\u003e\u003c/s\u003e\u003cs\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Hammond \u0026amp; Loghavi, 2021)\u003c/span\u003e\u003c/s\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122.6pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New 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style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e128\u003c/span\u003e\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Idrees \u0026amp; Kumar, 2021)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e129\u003c/span\u003e\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Young et al, 2020)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e130\u003c/span\u003e\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Chakrabarti et al, 2021)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e131\u003c/span\u003e\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Schultz et al, 2021)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino 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style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e141\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e(Hernandez-Lopez et al. 2023)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:justify;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e145\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Yang et al. 2022)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e153\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Bar-On et al, 2023)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e155\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Tamari et al, 2024)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 53.75pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e8. Excess acetylcholine pathway\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122.6pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122.65pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122.6pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e160\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Mudd et al, 2020)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e161\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Monneret et al, 2021)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e165\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Horkowitz et al, 2020)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122.65pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e169\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Erttmann et al, 2022)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e170\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Gabanyi et al, 2022)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e171\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Liu et al, 2022)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e157\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Shahbaz et al, 2023)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e158\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Lee et al, 2022)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e159\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Lee et al, 2023)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e164\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Shim, 2023)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e166\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;(Axenhus et al, 2022)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cu\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e167\u003c/span\u003e\u003c/sup\u003e\u003c/u\u003e\u003cu\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp; (Chen et al, 2023)\u003c/span\u003e\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;'\u003e*1: The original Preprint file (Supplement 2): Lee, J. (2022, January 14). Pathology and Anticatalysis treatment of exacerbated COVID-19. https://doi.org/10.31219/osf.io/t9wjz\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;'\u003e*2: Each one was checked and matched with the reference number of this paper.\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;'\u003e*3: In parentheses, the author and publication year are described to help distinguish the information in the paper.\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;'\u003e*4: Yellow represents papers published before 2020-2021 at the beginning of the pandemic.\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;'\u003e*5: The cited paper that used the strikethrough was removed during the 18th update because it did not reflect reality.\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;'\u003e*6:\u0026nbsp;\u003c/span\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eThe papers in bold black indicate the papers used from the beginning to the end.\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e*7: Underlined are papers submitted in 2022-2023. There is also a paper published in 2024.\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e*8: Paper No. 45, 89 in the 1\u003csup\u003est\u003c/sup\u003e version is excluded because it is a preprint.\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003e*9: Italics indicate cases where the cited paper has been moved to explain a different mechanism in reality.\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;text-align:left;line-height:normal;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:12px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin:0in;text-align:justify;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTable 2\u003c/span\u003e\u003c/strong\u003e\u003cspan style='font-size:16px;font-family:\"Times New Roman\",serif;'\u003e. The Immune Triad for Anticatalysis Treatment Against Exacerbations of COVID-19\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54.2pt;border: 1pt solid windowtext;padding: 0in 5.4pt;height: 37.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76.05pt;border-width: 1pt 1pt 1pt medium;border-style: solid solid solid none;border-color: windowtext windowtext windowtext currentcolor;border-image: none;padding: 0in 5.4pt;height: 37.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eAcetylation,\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003ecGAS-STING axis\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62.7pt;border-width: 1pt 1pt 1pt medium;border-style: solid solid solid none;border-color: windowtext windowtext windowtext currentcolor;border-image: none;padding: 0in 5.4pt;height: 37.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eNeutrophil,\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eIFN pathways\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86.9pt;border-width: 1pt 1pt 1pt medium;border-style: solid solid solid none;border-color: windowtext windowtext windowtext currentcolor;border-image: none;padding: 0in 5.4pt;height: 37.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eNETs\u003csup\u003e1\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59.9pt;border-width: 1pt 1pt 1pt medium;border-style: solid solid solid none;border-color: windowtext windowtext windowtext currentcolor;border-image: none;padding: 0in 5.4pt;height: 37.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eInflammasome\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.1pt;border-width: 1pt 1pt 1pt medium;border-style: solid solid solid none;border-color: windowtext windowtext windowtext currentcolor;border-image: none;padding: 0in 5.4pt;height: 37.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eILCs\u003csup\u003e4\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eCytokine\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60.25pt;border-width: 1pt 1pt 1pt medium;border-style: solid solid solid none;border-color: windowtext windowtext windowtext currentcolor;border-image: none;padding: 0in 5.4pt;height: 37.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eClinical results\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7pt;border-width: 1pt 1pt 1pt medium;border-style: solid solid solid none;border-color: windowtext windowtext windowtext currentcolor;border-image: none;padding: 0in 5.4pt;height: 37.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eRef.\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54.2pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eAspirin\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76.05pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eIFN\u003csup\u003eactive\u0026nbsp;\u003c/sup\u003e(\u003csup\u003e*\u003c/sup\u003e\u0026darr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62.7pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86.9pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59.9pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.1pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eILC2s (nasal mucosa\u0026uarr;, blood\u0026darr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60.25pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eMortality (\u0026darr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u003csup\u003e216\u003c/sup\u003e\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;'\u003e\u003csup\u003e217\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54.2pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;height: 88.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eDapsone\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76.05pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;height: 88.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eIFN\u003csup\u003eactive\u0026nbsp;\u003c/sup\u003e(\u0026darr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62.7pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;height: 88.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eIFN\u003csup\u003eactive\u0026nbsp;\u003c/sup\u003e(\u0026darr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86.9pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;height: 88.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eMPO-DNA NETs (\u0026darr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59.9pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;height: 88.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eNLRP3\u003csup\u003e3\u003c/sup\u003e (\u0026darr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.1pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;height: 88.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eILCs (\u0026darr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60.25pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;height: 88.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eMortality (\u0026darr;)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eNLR ratio (\u0026darr;)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eExacerbation (\u0026darr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;height: 88.85pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;'\u003e\u003csup\u003e12\u003c/sup\u003e\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u003csup\u003e218\u003c/sup\u003e\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u003csup\u003e219\u003c/sup\u003e\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u003csup\u003e220\u003c/sup\u003e\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u003csup\u003e221\u003c/sup\u003e\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u003csup\u003e222\u003c/sup\u003e\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u003csup\u003e223\u003c/sup\u003e\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u003csup\u003e224\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54.2pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eDexamethasone\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76.05pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62.7pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eIFN\u003csup\u003eactive\u0026nbsp;\u003c/sup\u003e(\u0026darr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86.9pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eimmature neutrophils (\u003csup\u003e**\u003c/sup\u003e\u0026uarr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59.9pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.1pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eblood ILC2s (\u0026darr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60.25pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eMortality (\u0026darr;)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eNLR ratio (\u0026darr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u003csup\u003e225\u003c/sup\u003e\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u003csup\u003e226\u003c/sup\u003e\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u003csup\u003e227\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 54.2pt;border-width: medium 1pt 1pt;border-style: none solid solid;border-color: currentcolor windowtext windowtext;border-image: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eCOVID-19\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76.05pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eIFN\u003csup\u003eactive\u0026nbsp;\u003c/sup\u003e(\u0026uarr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 62.7pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eIFN\u003csup\u003eactive\u0026nbsp;\u003c/sup\u003e(\u0026uarr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86.9pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003ecell-free DNA, MPO\u003csup\u003e2\u003c/sup\u003e-DNA complexes (\u0026uarr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59.9pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eNLRP3 (\u0026uarr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.1pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003eCD8+ T cells (\u0026uarr;)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60.25pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7pt;border-width: medium 1pt 1pt medium;border-style: none solid solid none;border-color: currentcolor windowtext windowtext currentcolor;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;text-align:center;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u003csup\u003e173\u003c/sup\u003e\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style='font-size:15px;font-family:\"Times New Roman\",serif;color:windowtext;'\u003e\u003csup\u003e174\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin:0in;text-align:justify;line-height:13.0pt;font-size:13px;font-family:\"Palatino Linotype\",serif;color:black;'\u003e\u003csup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;color:windowtext;'\u003e1\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-family:\"Times New Roman\",serif;color:windowtext;'\u003e) Neutrophil extracellular traps, \u003csup\u003e2)\u0026nbsp;\u003c/sup\u003emyeloperoxidase, \u003csup\u003e3)\u0026nbsp;\u003c/sup\u003eNLR family pyrin domain-containing 3 (previously known as NACHT, LRR, and PYD domain-containing protein 3 [NALP3] and cryopyrin), \u003csup\u003e4)\u003c/sup\u003e innate lymphoid cells, \u003csup\u003e*)\u0026nbsp;\u003c/sup\u003edecreased, \u003csup\u003e**)\u0026nbsp;\u003c/sup\u003eincreased\u003c/span\u003e\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e1\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Choudhury, A., Mukherjee, G. 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Interactions between the host and virus govern induction, resulting in multiorgan impacts. In 2021, as normal life was challenging during the pandemic era, we analyzed SCI journals according to L. Wittgenstein's Tractatus Logi-co-Philosophicus. The pathophysiology of coronavirus disease 2019 (COVID-19) involves the following steps: 1) the angiotensin-converting enzyme (ACE2) and Toll-like receptor (TLR) pathways: 2) the neuropilin (NRP) pathway, with seven papers and continuing with twenty-four: 3) the sterile alpha motif (SAM) and histidine-aspartate domain (HD)-containing protein 1 (SAMHD1) tetramerization pathway, with two papers and continuing with twelve: 4) inflammasome activation pathways, with five papers and continuing with thirteen: 5) the cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) (cGAS–STING) signaling pathway, with six papers and successful with eleven: 6) the spike protein pathway, with fourteen and continuing with twenty-three: 7) the immunological memory engram pathway, with thirteen papers and successive with eighteen: 8) the excess acetylcholine pathway, with three papers and successful with nine. We reconfirmed that COVID-19 involves seven (1-7) pathways and a new pathway involving excess acetylcholine. Therefore, it is necessary to therapeutically alleviate and block the pathological course harmoniously with modulating innate lymphoid cells (ILCs) if diverse SARS-CoV-2 variants are subsequently encountered in the future.\u003c/p\u003e","manuscriptTitle":"The picture theory of seven pathways associated with COVID-19 in the real world","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2024-04-08 18:48:00","doi":"10.21203/rs.3.rs-3849399/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2024-01-12 10:53:02","doi":"10.21203/rs.3.rs-3849399/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c9a53663-0779-45cd-817c-f4229242a50c","owner":[],"postedDate":"April 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-04-10T15:54:57+00:00","versionOfRecord":{"articleIdentity":"rs-3849399","link":"https://doi.org/10.1186/s12985-024-02506-8","journal":{"identity":"virology-journal","isVorOnly":false,"title":"Virology Journal"},"publishedOn":"2024-09-27 00:00:00","publishedOnDateReadable":"September 27th, 2024"},"versionCreatedAt":"2024-04-08 18:48:00","video":"","vorDoi":"10.1186/s12985-024-02506-8","vorDoiUrl":"https://doi.org/10.1186/s12985-024-02506-8","workflowStages":[]},"version":"v2","identity":"rs-3849399","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3849399","identity":"rs-3849399","version":["v2"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}