Plausibility of natural immunomodulators in the treatment of COVID-19-A comprehensive analysis and future recommendations.

All authors listed have significantly contributed to the development and the writing of this article.

Infectious diseases have been the leading causes of mortality and morbidity globally for centuries. They significantly affect public health and socioeconomic stability across the world. Most importantly, the emergence of new infectious diseases challenges researchers to discover and develop new drugs to treat them urgently. The current scenario of COVID-19 has posed a global threat to human lives and the economy and has already caused millions of deaths. In this review, a significant number of natural compounds that are enlisted still remained unexplored against the SARS-CoV-2 virus. These compounds can be investigated using molecular simulation and docking studies to identify their immunomodulatory actions for COVID-19 treatment. For instance, nicotine showed significant inhibitory effects on the pro-inflammatory cytokine release in the cancer cells and this effect could be explored for therapeutic action in COVID-19 infection. The high binding affinity of morphine and codeine for the SAR-COV-2 ACE receptor resulted in the docking studies that could be extended to the in-vivo and clinical trials to treat COVID-19 infection as future research. Gallic acid showed promise in selective inhibition of proinflammatory cytokines without hindrance to interferon production in several in-vitro studies. This selective action of gallic acid to suppress cytokine storm in COVID-19 patients could be evaluated using advanced molecular dynamic simulation or in-vivo or clinical studies. The immunostimulation effect of Scrocaffeside A could be studied in animal models to investigate its therapeutic action in COVID-19 infection. The anti-inflammatory effect of fucoidan is very promising for future docking, in-vitro, and in-vivo studies to explore its therapeutic application for this deadly viral infection. The immunomodulatory structure was identified in arisantetralones A-D (1–4) and arisanschinins F-L (5−11) indicating its substantial prospect for future research for treating COVID-19 infection. However, natural immunomodulators having limitations like poor bioavailability, biological incompatibilities, and non-selective action could be designed as nanotherapeutics to alleviate the possible adverse effects. Chloroquine is a natural compound undergoing clinical trials as a nanotechnology-based drug at present [ 253 ]. Likewise, the mentioned natural compounds in Table 2 can be studied as nanotechnology-based drugs to investigate their immunomodulatory action in COVID-19 infection. Due to possessing pivotal immunomodulatory actions, they justify their plausibility as target molecules for this deadly virus. Henceforth, our recommendation for the researchers is to investigate their potential immune-boosting effect and discover effective and safe drugs to treat SARS-CoV-2 virus. Due to possessing pivotal immunomodulatory actions, they justify their plausibility as target molecules for this deadly virus. Henceforth, our recommendation for the researchers is to investigate their potential immune-boosting effect and discover effective and safe drugs to treat SARS-CoV-2 virus.

SARS-CoV-2 enters the host cells by binding with the ACE-2 receptor, infects the cells, and then the innate immune responses trigger as the first line of defense against the virus. This response is because of the increased viral load and induces cell damage [ 34 ]. After entering, translation of SARS-CoV-2 RNA and viral replication occurs thus leading to lower respiratory tract infection [ [35] , [36] , [37] , [38] ]. Consequently, the host immune responses induced by the SARS-CoV-2 are antiviral immune responses with the helper T cells and cytotoxic T cells of the infected persons [ 39 ]. Another potent immunity is the programmed cell death of the infected cells [ 40 ]. In the initial immunity stage, the immune responses that protect the host are called innate immunity. In this step, activation of transcription factors results in the production of the Type-I and –III antiviral Interferons and different chemokines [ 41 ]. The production of cytokines is also induced, which warrants the recruitment of adaptive immunity cells [ 39 ]. CD4 + T cells and CD8 + T cells generate adaptive immune responses in COVID-19 infection [ 42 ]. The CD4 + T cells responses are more important than CD8 + T cells [ 43 ]. The plasma and cytotoxic T cells generate neutralizing antibodies, which secret cytokines to kill the virus-infected cells [ 44 ]. The cytokines, which are low molecular weight protein signaling molecules, can influence immunity [ 45 ]. The excessive cytokine release, called a cytokine storm, is one of the indicators of COVID-19 patients that can lead to tissue inflammation of the infected person [ [46] , [47] , [48] , [49] ]. The immune responses could be varied between pediatric and adult patients. That is why children and youths face more mild disease conditions than adults [ 50 ]. One study has investigated that cellular and humoral immune responses are distinct regarding the severity of COVID-19 disease [ 51 ]. During the humoral response, the antibodies act against the S protein and prevent viral entry to the vulnerable ACE2+ cells [ [52] , [53] , [54] , [55] ]. Among the antibodies, IgM and IgA can be identified after infection for seven days. On the other hand, IgG can be detected 14 days after the initiation of the symptoms [ 10 , 56 , 57 ]. It is crucial to know how long the protective action of these antibodies will be effective. The protective immune responses generated by the COVID-19 vaccine could fade away within time. The effectiveness decreased by six months after vaccination, whether someone had severe COVID-19 disease or a symptomatic one. Twenty-one percentage points lowered the efficacy for people of all ages but 20.7% points for older people [ 58 ]. The effectiveness can be increased after seconds who receiving the first dose. The COVID-19 vaccines (BNT162b2:mRNA vaccine or ChAdOx1 nCoV-19-Non:Viral vector vaccine [ 59 ] showed lower efficacy against alpha and delta variants after one dose but higher effectiveness after the second dose. Both vaccines have a 30.7% effectiveness with delta variants and 48.7% for alpha variants in the case of one dose. But after two doses among alpha and delta variants, the efficacy increased to 93.7% and 88.0% respectively with the BNT162b2 vaccine [ 60 ]. On the other hand, the vaccine effectiveness after full vaccination is shown higher in delta variants than in the omicron variants [ 61 ].

To date, no SARS-CoV-2 specific and accurate drugs are available to treat COVID-19 patients. However, it is evident that several drugs belonging to immune modulators, antiparasitic, antimalarial, antiviral, antibacterial, corticosteroids, and anticoagulants have been used as alternatives to treat infections caused by the SARS-CoV-2 virus [ [62] , [63] , [64] ]. For instance, ivermectin and doxycycline are used to treat COVID-19 infections in developing countries [ 62 ]. Ivermectin, an antiparasitic drug was used in the clinical trial of COVID-19 patients and the FDA recommended not to use this drug in COVID-19 patients regardless of illness severity since there is no persuasive evidence of the mechanism of anti -COVID action of this drug, thus would limit in explanation of clinical benefits achieved with it [ 65 ]. A combination of hydroxychloroquine and azithromycin has been used to treat COVID-19-infected patients across the globe with different outcomes [ 63 ] There is no concrete evidence to support the efficacy of azithromycin treatment in COVID-19 patients [ 66 ] or to modify the effect of hydroxychloroquine for any outcome [ 65 ]. Therefore, routine use of azithromycin will lead to increased antibiotic resistance [ 67 ]. Azithromycin is not currently used in COVID-19 patient treatment in combination with hydroxychloroquine. The use of antiviral drugs, lopinavir-ritonavir, remdesivir, favipiravir, and ribavirin to treat COVID-19 patients has been reported. Molnupiravir is an oral antiviral drug the FDA has given a conditional recommendation for its use in the treatment of adults with mild to moderate COVID-19, at the highest risk of hospitalization. However, the use of this drug in children (age <18) is prohibited due to its adverse effect in bone and cartilage growth [ 68 ]. One study demonstrated that lopinavir-ritonavir reduced disease symptoms at the early stage of the COVID-19 infection without any disease treatment acceleration [ 64 ]. However, another study demonstrated no treatment benefit was observed in lopinavir-ritonavir-treated hospitalized adult patients with severe COVID-19 infection [ 69 ]. In addition to that, an increased risk of bradycardia was reported with lopinavir-ritonavir treatment in patients with COVID-19 infections [ 64 ]. Although remdesivir and favipiravir accelerated patients’ recovery in the clinical study, cardiovascular side effects such as cardiac arrest, hypotension, atrial fibrillation, bradycardia, etc. Were reported for remdesivir whereas prolonged QT interval was reported with favipiravir [ 70 ]. Therefore, the use of these antiviral drugs might pose a challenge in cardiovascular practice [ 70 ]. In the case of ribavirin, no distinct treatment benefit or treatment advantage was observed in a clinical study [ 64 ]. Although the other two antiviral drugs; chloroquine phosphate and hydroxychloroquine showed positive outcomes in COVID-19-infected patients, the risk of arrhythmia is associated with their administration, and caution is required to use at higher cumulative doses. Thus, the FDA recommended the use of these drugs in hospitalized patients with severe COVID-19 infection [ 65 ]. In the case of treatment with oseltamivir, no benefit or no factual data were provided on the effectiveness of the medication. Arbidol hydrochloride, a broad-spectrum inhibitor of influenza A and B virus, is used in China and Russia, but no conclusive evidence of its efficacy was reported [ 69 ]. Immunomodulators such as convalescent plasma, baricitinib, and tofacitinib [ 71 ] have also been applied to COVID-19 patients since severely infected patients were diagnosed with a high plasma level of cytokines and worsened immune response. Potential risks of convalescent plasma therapy include increased thrombotic events, the selection of donors with high neutralizing antibody titers, and a lack of high-quality research in this field [ 69 ]. Baricitinib reduced COVID-19-induced inflammatory responses and showed greater efficiency when administered with remdesivir, and lopinavir-ritonavir. But the main concern with this drug is the possibility of producing anemia in treated COVID-19 patients. Rofacitinib, a JAK (Janus kinase) inhibitor was used in the clinical trial and the result demonstrated a higher reduction of mortality (70%) of COVID-19 patients compared to dexamethasone treatment (Hayek et al., 2021) and obtained conditional FDA recommendation for patients with severe or critical COVID-19 [ 64 ]. Considering the severity of COVID-19 infections, drugs with anti-inflammatory properties such as corticosteroids; dexamethasone, and prednisolone have been used in COVID-19 patients with severe and critical conditions [ 64 ]. The World Health Organization (WHO) and the United States Centers for Disease Control and Prevention (CDC) recommended that corticosteroids should not be used regularly to treat COVID-19 patients unless patients have asthma, COPD exacerbation, or septic shock because hypernatremia, hypokalemia, and hyperglycemia are associated with routine use of corticosteroids [ 69 ]. Apart from these, interleukin inhibitors (Ankira: IL-1 receptor antagonist; Tocilizumab: Human monoclonal antibody and IL-6 inhibitor), anticoagulants (Heparin, Nafamostat mesylate), have been used in hospitals to treat COVID-19 patients [ 64 ]. These immunomodulators showed significant clinical responses, reduced inflammatory responses via reduction of the inflammatory markers, and reduced overall mortality [ 64 ]. However, data lacks to identify the most effective and safest immunomodulator in COVID-19 treatment [ 72 ]. Thus, due to the limitations of current therapeutics, there is an urgent need to discover and develop novel drugs with selectivity, safety, and efficacy using natural products for treating COVID-19 infection.

Despite the availability of novel vaccines for SARS-CoV-2, searching for novel, effective, and safe drugs for treating this disease is crucial until the vaccines are proven effective to reduce mortality and morbidity and become available for the entire population [ 87 ]. Given the mortality and morbidity of COVID-19 due to disrupting normal immune responses of severely and critically infected COVID-19 patients, drugs that can ameliorate hyperimmune and hyperinflammatory states to intercept disease prognosis and worsening must be urgently sought [ 12 , 87 ]. The modulation of immune responses to assuage diseases has been of paramount importance for many years. Natural products with promising immunomodulatory potential are receiving adequate attention nowadays [ 88 ]. The Discovery of plant-derived immunomodulatory agents with augmented bioavailability and substantially devoid of toxic effects opens a new approach to alleviate observed cytokine storm syndrome in COVID-19 [ 89 , 90 ]. Immunomodulators can stimulate, suppress, or modulate various aspects of the host's immune system, including innate and adaptive immune systems [ 91 ]. Considering the interplay between the immune-inflammatory axis and viral infection, natural products with immunomodulatory and anti-inflammatory actions are proposed to explore as COVID-19 preventives and therapeutics [ 92 ]. Drug research and development are currently based on biochemicals, biologics, and single compounds considered a lead compound against a disease treatment. However, it is impossible to obtain a single compound with high potency and low toxicity to target a cellular pathway causing the disease [ 93 ]. In these circumstances, the natural compounds with promising immunomodulatory action could be used as a lead or template for novel drug discovery and development. The immunomodulatory compounds isolated from the plant extract could replace synthetic compounds that exert substantial side effects. Table 1 summarizes the investigation findings of a significant number of natural compounds using different study models against SARS-CoV-2. Below is a detailed discussion on promising natural compounds with immunomodulatory potential against SARS-CoV-2. Fig. 2 shows the mechanism of immunomodulatory action of different natural compounds against COVID-19 infection. Hence, the following subsections will delineate natural products with promising immunomodulatory activity along with their molecular mechanisms. Table 1 List of natural compounds that are already identified as immunomodulators against SARS-CoV-2. Table 1 Class Compound Source Mechanism of action Studied models References Alkaloid and its derivatives Alkaloid Colchicine Inhibition of NLRP3 inflammasome SARS-CoV-2 patients [ [94] , [95] , [96] , [97] , [98] ] Alkaloid Piperine Piper nigrum L. Significant binding affinity toward the spike glycoprotein of SARS CoV-2 and the ACE2 receptor Docking study; in-vitro calcium-mediated fusion of lipid vesicles induced by fragments of MERS-CoV and SARS-CoV/SARS-CoV-2 fusion peptides; in-vitro study of SARS-CoV-2 against Vero cells; clinical trials [ 103 , 104 , 181 ] Aporphine alkaloid Magnoflorine T. cordifolia Inhibition of SARS-COV2 Mpro Multiple docking studies [ 105 ] Isoquinoline alkaloid Berberine T. cordifolia Inhibition of SARS-COV2 Mpro Multiple docking studies [ 105 , 110 ] Flavones Flavone Myricetin Aglaia perviridis Inhibition of SARS-CoV-2 3CLpro Inhibition of ATPase activity of the SARS-CoV helicase protein, NSP13 FRET assay using recombinant SARS-CoV-2 3CLpro Colorimetric-based ATP hydrolysis assay [ 111 , 112 ] Scutellarein Phseudolysimachion longifoiium, Scutellaria lateriflora, Asplenium belangeri Inhibition of SARS-CoV-2 Mpro; inhibition of ATPase activity of SARS-CoV NSP13 FRET assay, Colorimetric-based ATP hydrolysis assay [ 112 , 117 , 236 ] Flavonone glycoside Hesperidin Citrus fruits; citrus foods-derived products Target the interaction site between SARS-CoV-2 Spike and ACE2 receptors, thus blocking the entry of the virus into the human lung cells. In-silico study; Vero cells; young children and infants exposed to rotavirus [ 118 ] Flavonoids Flavonoid Apigenin Parsley, celery, onions, oranges, chamomile, maize, rice, tea, wheat sprouts, some grasses, etc Inhibition of SARS-COV2 Mpro In-silico docking studies; in-vitro study with SARS-CoV 3 CLpro using fluorescence resonance energy transfer analysis [ 128 , 129 ] Chrysin Propolis, honey, cereals, passion flowers, red and yellow fruits, and vegetables Inhibition of SARS-COV2 Mpro Docking studies [ 134 ] Epi-catechin-gallate Green tea ( C. sinensis ) in-vitro inhibitory effect against the SARS-CoV-2 papain-like protease (PLpro) activity Differentiated Caco-2 Cells, docking study [ 117 ] Fisetin Plants like the smoke tree and numerous types of fruits and vegetables including strawberries, grapes, onions, and cucumbers 3CLpro and ACE2 of SARS-CoV-2 docking studies; ongoing clinical trial [ 117 ] Kaempferol Edible and medicinal plants 3 A ion channel of SARS-CoV-2 docking study [ 137 ] Luteolin Vegetables (celery, parsley, broccoli, carrots, peppers, and cabbages); fruits (apple skins); flowers (chrysanthemum), and in medicinal herbs such as Torreya nucifera Inhibition of SARS-CoV 3CLpro with IC 50 of 20.2 μM in-vitro ethanolic extract of T. nucifera against SARS-CoV 3CLpro [ 129 ] Naringenin Citrus fruits Inhibition of hTPC2 of SARS-COV2 Vero E6 cells infected with SARS-CoV-2 [ 155 ] Rutin Plants, apples, and tea leaves Inhibition of SARS-CoV-2 ACE2 receptor Multiple docking studies [ 157 ] Flavonoid-7-o-glucosides Apigenin-7-glucoside Lobelia chinesis, Teucrium gnaphalodes, and dandelion tea Inhibition of SARS-CoV-2 Mpro In-silico study [ 128 , 160 ] Polyphenolic flavonoid Quercetin Broccoli, red onions, eggplant, potatoes, and green leafy vegetables including celery, lettuce; fruits including apples, citrus fruits, red grapes, tomatoes; berries including cranberries and raspberries Inhibition of SARS-CoV-2 ACE2 receptor FRET assay using recombinant ACE2 and Mca-APK(Dnp) as the substrate; clinical trials [ 171 , 181 , 184 , 214 ] Polyphenols Polyphenols Catechin Green tea, Korean tea, black tea, wine, coconuts, onion, grape seeds, etc. Blockade of early steps of viral life cycle Docking studies with MPro of SARS-CoV-2. [ 172 ] Polyphenols Curcumin Turmeric Inhibition of S glycoprotein and ACE2 Vero E6 infected with SARS-CoV-2 and in-silico analysis [ 103 , 181 ] Polyphenolic phytoalexin Resveratrol Grapes, cranberry, blueberry, mulberry, peanuts, jackfruit, soy, and wine Inhibition of SARS-CoV-2 viral entry Live SARS-CoV-2 infection of Vero cells; clinical trial [ [182] , [183] , [184] , [185] , [186] ] Phenolic compound Oleuropein Olive (fruit and oil) Inhibition of the NSP15 endoribonuclease activity of SARS-CoV-2 Docking studies [ 187 , 188 ] Beta-hydroxy ketone Gingerol Zingiber officinale (common name ginger) Multi-site inhibition of SARS-CoV-2 Mpro, inhibition of spike protein of SARS-CoV-2 and inhibition of SARS-CoV E protein Multiple docking studies, clinical trial [ [210] , [211] , [212] , [213] ] Aromatic oil Eugenol Cinnamon bark and leaves, tulsi leaves, turmeric, pepper, ginger and organic herbs like oregano, thyme, basil, etc. Prevention of viral entry into host cells by binding with SARS-CoV-2 ACE2 receptor, envelope protein, spike protein and membrane protein Multiple docking studies [ 225 ] Carotenoid Astaxanthin Haematococcus pluvialis Inhibits the SARS-CoV-2 PLpro In-silico docking studies [ 207 ] Terpenoids Labdane diterpenoid Andrograph- olide Andrographis paniculata Inhibition of SARS-COV-2 Mpro Docking studies against SARS-COV-2 Mpro; clinical trial [ 208 ] Steroid glycosides/triterpene saponins Floralginsenosides B Panax ginseng Inhibition of SARS-CoV-2 receptor-binding domain (RBD) Docking studies [ 212 ] Triterpenoid Glycyrrhizin Licorice radiata Inhibits the SARS-COV2 Mpro Docking studies against SARS-CoV-2 Mpro and RdRp [ 215 , 216 ] Opiate Alkaloid Morphine Poppy seeds (P. somniferum) Inhibits cytokine release by binding to SARS-CoV-2 ACE receptors Swiss–Webster, C57BL/6 J rats, CB6F1 male mice; lung resident cells; male Swiss mice; docking study against ACE receptor, Clinical trial, Case-study [ 7 , 220 , 221 ] Miscellaneous Thiosulphate Allicin Garlic ( Allium sativum) Inhibition of SARS-CoV-2 Mpro Docking studies against SARS CoV-2 Mpro [ 185 ] Phenylpropene disaccharides Cordifolioside T. cordifolia Inhibition of SARS-CoV2 Mpro Multiple docking strategies [ 105 ] Tryptophan-derived Melatonin Herbs, Black pepper, corn seeds, rice, black and white mustard, Wolfberry, fennel, sunflower, fenugreek, Barkey, almonds, coriander, poppy, celery, anise, coffee beans etc inhibition of NLRP3 inflammasome activation; Inhibition of MCP1, CCL5 and CCL9 mRNA expression; downregulated the cytokine storm in COVID-19 b y reversing aerobic glycolysis Mechanistic study in immune cells of COVID-19 patients; multi-site clinical trials [ 8 , [235] , [236] , [237] , [238] , 240 ] Steroidal lactones Withanone Withania somnifera Significant interruption of electrostatic interactions between the RBD and ACE2; Inhibition of SARS-CoV-2 Mpro Docking studies; zebra fish [ 206 , 234 , 235 ] Fig. 2 Schematic representation of the mechanism of action of natural immunomodulators against SARS-CoV-2. Fig. 2 List of natural compounds that are already identified as immunomodulators against SARS-CoV-2. Schematic representation of the mechanism of action of natural immunomodulators against SARS-CoV-2. Colchicine, an alkaloid present in Colchicum autumnale , was approved by FDA in 2009 for the treatment and prevention of acute gout, familial Mediterranean fever, pericarditis, and other inflammatory conditions due to its strong anti-inflammatory effect [ 94 ]. Inflammasomes are a key feature of SARS-CoV-2 induced innate immune response and the extent of inflammasome activation especially, the nucleotide binding domain (NOD)-like pyrin domain 3 (NLRP3) inflammasome, is dependent on the severity of COVID-19 infection. Colchicine is cheap, promptly available, safe, and has inhibitory potential against NLRP3 inflammasome, thus offering itself as an attractive candidate for testing the role of the inflammasome in COVID-19 [ 112 , 113 ]. Several clinical trials on COVID-19 patients using colchicine have been done in different countries across the world. Lopes and her coworkers have found that colchicine reduced the duration of hospitalization and supplemental oxygen therapy, and the drug was also found safe and well tolerated [ 96 ]. A case-control study on patients with moderate to severe COVID-19 infection with colchicine demonstrated improved outcomes in patients taking the standard of care therapy [ 97 ]. Colchicine was also reported to significantly improve the time to clinical deterioration in patients with COVID-19 infection [ 98 ]. It has been suggested that treatment with colchicine in outpatients can significantly reduce the risk of hospitalization, morbidity, mortality, and demand for expensive medicines and special care resources [ 94 ]. On the contrary, short course colchicine treatment along with standard care showed no clinical benefit among 240 hospitalized COVID-19 patients [ 99 ]. Similarly, in another study, short duration of first 48 h of colchicine administration has produced no clinical improvement or inflammatory response in the COVID-patients who were hospitalized [ 100 ]. Piperine, an alkaloid presents in Piper nigrum (black pepper), present in approximately 2–7.4%, and is responsible for the distinctly sharp flavor of black pepper [ 101 ]. The black pepper is one of the most widely used spices in the world and is not only used in culinary preparations but also in medicinal and perfume preparations. It has well-established pharmacological effects encompassing anti-inflammatory, antiviral, anti-diabetic, antioxidant, anti-aging, anti-microbial, anti-allergic, cardio-protective, hepatoprotective, neuroprotective, antitumor, and immuno-modulatory functions alone, and in combination with other drugs assists in chronic disease management such as in the improvement of hepatic steatosis and depression [ 101 , 102 ]. Its effect has been studied in several in-vitro and in-vivo models-the mice model, PBMC, murine macrophages, and melanoma cells [ 7 ]. This natural bioactive has the potential to reduce Th2 cytokines IL-4, IL-5, IL-1β, IL-6, IL-10, IL-2, IFNγ, TNFα, and GM-CSF, in addition to inhibiting nuclear transcription factor κB (NF-κB), AMPK, and MAPK activation along with the amplification of IL-10 level. Reduction of the nuclear translocation of p65, p50, c -Rel subunits of NF-κB and other transcription factors ATF-2, c -Fos, and CREB [ 7 ]. In a docking study against SARS CoV-2, piperine exhibited a significant binding affinity toward the spike glycoprotein and ACE2 receptor with docking scores of −104.56 and −112.83 kcal/mol, respectively [ 103 ]. In a separate in-vitro study, piperine inhibited the fusion of lipid vesicles mediated by both fusion peptides of SARS-CoV/SARS-CoV-2 and the antiviral evaluation of 1.56–100 μg/mL of piperine using Vero cells infected with SARS-CoV-2 led to a significant decrease in the titer of SARS CoV-2 progeny, thus demonstrating its antiviral activity [ 104 ]. Clinical trials of co-administering curcumin and piperine are covered under “curcumin”. Magnoflorine (an aporphine alkaloid) and berberine (an isoquinoline alkaloid) are found in Tinospora cordifolia and are known for their reduction of TGF-β and TNF-α [ 105 ]. In multiple docking studies, magnoflorine and berberine inhibited the SARS-CoV-2 Mpro with docking scores of −6.4 and −6.8 kcal/mol, respectively, and binding energies of −14.18 and −17.92 kcal/mol, respectively, and thus impact viral replication and transcription [ 105 ]. In COVID-19 patients, mortality was associated with fluid filling up in the lungs, because of the cytokine storm [ 106 ]. Also, in most COVID-19 patients, elevated TGF-β [ 107 , 108 ] and TNF-α [ 9 , 109 ] were associated with severe disease states. As a result, in a separate docking study involving biomarkers TGF-β and TNF-α, interactions and binding energies of cordifolioside, magnoflorine and berberine were studied and among them, cordifolioside was proven to be more stable than the other two [ 105 ]. Berberine was found to reduce the risk of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in COVID-19 patients by inhibiting proinflammatory cytokine release and inflammatory signaling pathways [ 110 ]. However, no clinical trial was conducted with magnoflorine in COVID-19 infected patients to confirm its outcomes to combat this virus. Myricetin is a dietary flavone, present in several fruits such as berries and nuts, and can also be obtained from the Aglaia perviridis. It has strong antioxidant and anti-inflammatory potential and was found to inhibit SARS-CoV-2 (IC 50 value 3.684 ± 0.076 μM) by binding with the SARS-CoV-2 Mpro as observed in the FRET-based assay and the binding free energy of myricetin with SARS-CoV-2 Mpro was calculated to be −32.98 kcal/mol, using the MMGBSA method [ 111 ]. Additionally, in colorimetric-based ATP hydrolysis assay, myricetin was found to likely interfere with ATPase activity of the SARS-CoV helicase protein, nsP13, possibly by directly interacting with critical residues of the ATPase domain, such as N265, Y269, and R443 [ 112 ]. In mouse primary macrophages and RAW264.7 monocytic cell-line, myricetin was found to inhibit the lipopolysaccharide (LPS)-induced interleukin (IL)-12 production in a significant manner through down-regulation of NF-κB binding activity [ 113 ]. And an in-vitro investigation revealed that myricetin significantly affects IL-2 expression [ 114 ]. More studies need to be conducted to determine its immunomodulatory role in-vivo . Scutellarein is a flavone that gives a characteristic bitter taste in mexican oregano and sweet orange and is also present in various Scutellaria species, including ferns like Asplenium belangeri and Pseudolysimachion longifolium [ 115 ]. Scutellarein was also found to significantly inhibit NO production and reduced the mRNA expression levels of inducible NO synthase (iNOS) and tumor necrosis factor (TNF)-α in lipopolysaccharide (LPS)-activated RAW264.7 cells [ 116 ]. Additionally, it also caused a decrease in the phosphorylation levels of different upstream signaling enzymes involved in the NF-κB activation. Finally, it strongly inhibited Src kinase activity and inhibited the autophosphorylation of overexpressed Src [ 116 ]. Using FRET assay, the inhibitory effect of Scutellarein and its analogues were studied against SARS-CoV-2 Mpro and it was found that one of its analogue, 4′- O -methylscutellarein showed the 50% inhibition at a lower concentration (IC 50 value 0.40 ± 0.03 μM) compared to scutellarein which showed 50% inhibition at 5.68 ± 0.48 μM [ 131 ]. Also, it inhibited the ATPase activity of SARS-CoV NSP13 as studied via the colorimetric-based ATP hydrolysis assay [ 117 ]. However, in-vivo and clinical trials are required to determine the role of scutellarein in SARS-CoV 2 infection. Hesperidin is a flavonone glycoside found in many citrus fruits. Recently, an in-silico docking study revealed that hesperidin showed the highest docking score when targeted against SARS-CoV-2 Spike and ACE2 receptors, thus, blocking the entry of the virus into the human lung cells [ 118 ]. In the same study, they synthesized hesperidin Zinc Oxide nanoparticles (ZnO NPs) which also demonstrated competitive good docking scores when targeted against SARS-CoV-2 Spike and ACE2 receptors. The two samples of hesperidin and ZnO NPs showed 50% cell cytotoxic concentration (CC50) = 620.8 ± 34.6 and 243.7 ± 12.7 μg/mL, respectively. Thereafter, its in-vitro antiviral activity was evaluated using Vero cells (derived from African green monkey kidneys obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA)) infected with hepatitis A virus at the maximum non-toxic concentration (MNTC) using plaque assay method. It was found that the hesperidin ZnO nanoparticles showed greater activity than hesperidin alone. Moreover, in infected mice (acute lung inflammation induced by LPS in-vivo) it was found to cause the suppression of TNF-α, IL-1β, IL-6, IL-8, IL-12, and NO expression, down-modulation of ROS production and CD14 and adhesion molecules expression while increasing the CD4+/CD8+ cell ratio in mice models. Furthermore, young children and infants exposed to rotavirus were also treated with hesperidin for immunomodulatory activity against the virus and found the IC 50 of hesperidin was 10 μM [ [119] , [120] , [121] ]. Therefore, this makes hesperidin and hesperidin ZnO nanoparticles great candidates for further testing against SARS-CoV-2. Randomized double-blinded clinical trial with 1000 mg hesperidin once daily for 14 days was conducted in symptomatic non-vaccinated COVID-19 patients and the findings demonstrated this natural compound may help reduce fever, cough, shortness of breath, and anosmia. Hesperidin was also found safe for the patients [ 122 ]. Apigenin is a flavonoid present in vegetables such as parsley, celery, onions, and in rice, maize, and wheat sprouts. Its immunomodulatory effect has been studied in-vitro murine and human autoimmune T-cells-and in-vivo animal studies-mouse model and rat colitis-apigenin inhibit the IL-6, IL-10, and INF-γ, while stimulating the TNF-α. It also reduces the response of Th1 (T-helper 1) and Th17 cells. Additionally, it inhibits the NF-κB activation pathway, suppresses the NF-κB translocation to the nucleus, inhibits the I-κBα phosphorylation and degradation in response to T-cell receptor (TCR) stimulation in reactivated peripheral blood CD4 T-cells as well as in leukemic Jurkat T-cell lines. This leads to a reduction of eosinophil count [ [123] , [124] , [125] , [126] , [127] ]. Furthermore, in an in-silico docking study, apigenin inhibited the main protease of SARS-CoV-2 with a docking score of −7.2 kcal/mol [ 128 ]. Also, in an in-vitro study, using fluorescence resonance energy transfer analysis, it was found that apigenin inhibited SARS-CoV 3CLpro activity with IC 50 values of 280.8 μM [ 129 ]. Olive leaves containing different phenolic compounds including apigenin-7-glucoside are regarded as anti -SARS-CoV-2 metabolites which have the potential to improve symptoms such as oxygen saturation, viral clearance in COVID-19 patients [ 130 ]. Chrysin is another flavonoid found majorly in honey and then in cereals, red and yellow fruits, among many. Its immunomodulatory activity has been studied on LPS-stimulated splenocytes, experimental autoimmune uveitis (EAU) in C57BL/6 J mice, Dextran Sodium Sulfate (DSS)-induced colitis in BALB/c mice and murine WEHI-3 leukemia cells [ [131] , [132] , [133] ]. It was shown to enhance the NK cell and CTL activities while inhibiting the production of inflammatory cytokines such as IFN-c and TNF-α by activating macrophages through the NF-κB pathway. Moreover, it causes inhibition of serum levels of NF-κB, p65 unit, tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-12, IL-17 A, interferon-gamma (IFN-γ), conversely, enhancing CD3 (T-cell marker) and CD19 (B-cell marker) [ [131] , [132] , [133] ]. In docking studies, chrysin inhibited the SARS-CoV-2 Mpro activity with a docking score and potential energy of −6.097 and −63.126 kcal/mol [ 134 ]. No clinical trials have been conducted on chrysin yet, despite being abundant as a natural immunomodulant in honey. Epi-catechin-gallate is present in green tea, Clonorchis sinensis (C. sinensis), and its antiviral activity against SARS-CoV-2 has been studied in-vitro in differentiated Caco-2 cells and in docking studies, whereby it has been shown to inhibit the SARS-CoV-2 papain-like protease (PLpro) activity through trans -epithelial transport of green tea ( C. sinensis ) with an IC 50 value of 0.125 μg/mL [ 117 ]. It is involved in a wide variety of immunomodulatory pathways in the oral cavity, especially in the pulp and gingival cells and its activity in-vivo needs to be studied to better understand its impact beyond the oral cavity [ 135 ]. Fisetin is a flavonoid present in plants such as the smoke tree and numerous fruits like strawberries, grapes, and cucumber. Hosseinzade et al. (2019) [ 125 ] conducted multiple studies which showed the prowess of fisetin to not only inhibit Th1 and Th2 cytokine production, cell cycle, and the ratio of CD4+/CD8+ T cells but also suppress the nuclear factor kappa B activation and nuclear factor of activated T cells. In turn, it leads to the suppression of the NF-κB signaling pathway. Additionally, it inhibits the infiltration of inflammatory cells, including eosinophils, mast cells, and CD4 + and T CD8 + T cells. This, in turn, causes a decreased CD4 + T cell-induced production of INF-γ and IL-4 and stimulation of IL-10 level [ 125 ]. Fisetin, a bioactive immunomodulatory compound, decreases the number of infiltrating neutrophils and affects the self-renewal, division, proliferation, and survival of immune cells (such as monocyte and dendritic cells) [ 136 ]. In 2022, Wang and colleagues used systems pharmacology to determine the potential effect of 255 “representing flavonoids” using a wide array of algorithms and docking studies on 3CLpro and ACE2 of SARS-CoV-2 and they found fisetin to have binding energies of −7.354 kJ/mol and −7.563 kJ/mol, respectively [ 137 ]. It triggers caspase-3 and caspase-8 activation and lyse of polymerase (ADP-ribose), leading to induction of apoptosis [ 138 ]. Furthermore, fisetin has been used as a senolytic agent for the treatment of various chronic diseases such as respiratory disease, diabetes, and obesity [ 139 ]. An ongoing Phase 2 placebo-controlled, double-blind, randomized, pilot study is ongoing [ 140 ] to understand the effect of fisetin in SARS-CoV-2 patients to alleviate dysfunction and excessive inflammatory response in hospitalized adults [ 140 ]. Kaempferol is another flavonoid found in edible and medicinal plants. Hofer et al. (2020) conducted studies on human PBMC and Rho et al. (2011) on THP-1 cells. They found that kaempferol inhibits the NO production with an IC 50 of 7.58 μM by suppressing the iNOS mRNA expression, stimulates the nuclear factor kappa B (NF-κB) signaling, and increases the IL-1β, & TNF level, while down-regulating IL-6 [ 126 , 141 , 142 ]. To determine its effect against SARS-CoV-2, docking studies revealed that kaempferol inhibited the 3 A ion channel of SARS-CoV [ 137 ]. Further studies are necessary to determine its efficacy in in-vivo and clinical settings. Luteolin is a dietary flavonoid present in vegetables such as thyme, carrots and celery, apple skins, flowers such as in chrysanthemum, and medicinal herbs such as in Torreya nucifera (T. nucifera) . It has been traditionally used in Chinese medicine due to its anti-cancer, anti-inflammatory, anti-apoptotic as well as antioxidant activity [ 143 , 144 ]. It is currently used as an anti-inflammatory medication in autoimmune diseases such as multiple sclerosis and experimental autoimmune encephalomyelitis [ [145] , [146] , [147] ]. Luteolin is also known to provide neuroprotection in mouse models with traumatic brain injury [ 148 ]. As such it has found wide utility in studying various brain diseases due to its ability to cross the blood-brain barrier. Not only this but its immunomodulatory activities have also been extensively studied in vitro -in LPS/IFN-induced primary microglia and BV-2 microglial cells and PMA plus A23187-induced HMC-1 cellsand in vivo in MSU-induced inflammation in rats. Luteolin causes suppression of TNFα, IFNγ, IL-6, IL-8, IL-1β, CXCL8, GM-CS, and VEGF levels, while causing inhibition of NF-κB, STAT1, and IRF1. Moreover, it inhibits the JNK phosphorylation and has been shown to reduce TNF-induced mRNA expression of the NFKB1 and RELA genes [ 7 , 149 , 150 ]. Furthermore, in another study, the ethanolic extract of T. nucifera leaves exhibited a good inhibitory effect of 62% at 100 μg/mL, which was later fractionated and using fluorescence resonance energy transfer analysis, it was found that luteolin present in the leaves, inhibited the SARS-CoV 3CLpro at 20.2 μM [ 129 ]. More research on this is necessary, to determine its effect specifically against SARS-CoV-2. Naringenin is present in citrus fruits and tomatoes. Its immunomodulatory activity has been studied on LPS-stimulated whole blood cells of humans, macrophages, and splenocytes. It was found to inhibit IL-1β, TNF-α, IL-6, and IL-8 levels while inducing B cell proliferation and enhancing NK activity. The significant proliferation of T cells induces CTL activity, thereby inhibiting cellular oxidation in macrophages. It also causes down-regulation of GM-CSF, TNF, IL-1β, IL-1α, IL-6, IL-12p70, and IL-10 level, and enhanced protein and mRNA gene transcript expressions of TLR2 and TLR4, while inhibiting the p38 Mitogen-Activated Protein Kinase (MAPK) pathway [ [151] , [152] , [153] , [154] ]. In an in vitro study, Vero E6 cells were infected with SARS-CoV-2 it was found that naringenin inhibited hTPC2 of SARS-CoV-2 [ 155 ]. Recently, naringenin was discovered as an endolysosomal two-pore channel inhibitor and its potential role in SARS-CoV-2 infection was described in further detail [ 156 ]. It would be interesting to determine its effect in vivo . Rutin is a flavonoid present in apples, tea leaves, and plants. It binds to the S1 subunit of S -protein, PLpro, RdRp, and Mpro of SARS-CoV-2 with binding energies of −7.9, −7.7, −8.6, and −8.9 kcal/mol, respectively, and inhibition constant of 5.81, 5.66, 6.33, 6.54 μM, respectively [ 157 ]. Thus, it can block the entry of the RNA template, RdRp as well as the entry of the virus by binding to the S1 subunit. It works by decreasing the IL-1β, TNF-α, IL-6, and NO levels as observed in rat macrophages [ 158 ]. Apigenin-7-glucoside is a flavonoid-7-o-glucoside found in Lobelia chinesis , Teucrium gnaphalodes , and dandelion tea. In 2015, it was approved for prescription in the treatment of upper respiratory tract infections due to its strong anti-inflammatory potential [ 159 ]. It has some notable studies based on its immunomodulatory activity both in vitro -on splenocytes and RAW264.7 macrophages and in vivo -via acute lung injury in mice as mentioned by K.-C. Li et al. (2015) and Nasr-Bouzaiene et al. (2016) [ 160 , 161 ]. In such models, the IC 50 value for apigenin-7-glucoside was found to be 9.93 ± 1.32 μM, and it has been seen to enhance the activity of natural killer (NK) cells and cytotoxic activity of the T lymphocyte (CTL) while downregulating the oxidative enzyme expression and protein activation through inhibition of MAPK phosphorylation. Additionally, it inhibits the NF-κB (IκB) pathways [ 160 , 161 ]. Recently, in an in-silico docking study, apigenin-7-glucoside revealed strong binding contacts in the two active pockets of a target protein of SARS-CoV-2 Mpro with the docking scores and highest binding energies of −7.8 kcal/mol [ 160 ], while its synthetic analogue, apigenin-7-glucoside- p -coumarate, revealed a higher docking score of −8.8 kcal/mol against SARS-CoV-2 Mpro [ 128 ]. Both candidates are potential candidates for further testing clinically. Quercetin is a polyphenolic flavonoid present in a variety of fruits and vegetables. Its immunomodulatory function has been studied in mouse macrophages, influenza A-treated MDCK cells, BPMC, RAW 264.7 cells as well as on Human retinal pigment epithelial (ARPE-19) cells [ 7 , 125 , [162] , [163] , [164] , [165] ]. It is a potent immunosuppressant. It inhibits the release of pro-inflammatory cytokines (TNFα, Il-1β, Il-4, Il-5, IL-6, IL-8, G-CSF, GM-CSF, VEGF MCP1, ICAM1) and chemokines (IP10 and MCP1), it enhances anti-inflammatory cytokine IL-17 level and stimulates T-helper cells to produce IFNγ. It also suppresses the activation of ERK and p38 MA P kinase and NF-κB/IκB signal transduction pathways as well as causes inhibition of different signaling pathways, MAPKs, (IKK)α/β, c -Jun, CREB, activating transcription factor 2 (ATF2) and nuclear factor (NF)-κB p65, and blocks the translocation of NF-κB p65 into the nucleus [ 7 , 125 , [162] , [163] , [164] , [165] , [166] ]. Quercetin and its derivatives have well-established dose-dependent antiviral activity against rhinovirus replication, influenza virus, ebola, zika, hepatitis B and C as well as Epstein-Barr virus (EBV) owing to their ability to inhibit viral entry and replication within host cells [ 167 , 168 ]. They prevent further inflammation via inhibiting the activation of NLRP3 inflammasome via TXNIP pathway [ 169 ]. In a separate review study, coadministration of quercetin with ascorbic acid was suggested for “prophylaxis and the early treatment of respiratory tract infections” [ 168 ]. As such it has shown to inhibit the ACE2 of SARS-CoV-2 as observed in the FRET assay using recombinant ACE2 and Mca-APK(Dnp) as the substrate [ 157 ]. Complementary treatment of COVID-19 patients with quercetin after a week demonstrated speedy recovery compared to the control group. Quercetin decreased the SARS-CoV-2 persistence in the treatment group by 68% whereas the virus persistence reduction was only 24% in the control group [ 170 ]. In 2020, a randomized, parallel, open study was conducted to investigate the effect of quercetin on prophylaxis and treatment of COVID-19 [ 168 ] among 447 individuals but the outcome of the trial is still unavailable [ 171 ]. Similarly, in 2021, a separate early phase clinical trial [ 168 ] is ongoing to demonstrate the effect of quercetin on SARS-CoV-2 patients [ 167 ]. The outcome of the trial will help us fully understand its clinical efficacy. Catechin belongs to a group of compounds called polyphenols and is present in green, black, Korean tea, coconuts, and grape seeds. In a docking study, catechin was found to inhibit the MPro of SARS-CoV-2 [ 172 ]. Furthermore, in LPS-treated rat macrophages, catechin enhances IL-10 release while inhibiting TNFα and IL-1β while reducing NFκB activity in PMA-induced Jurkat T cells. It also led to the activation of the MAPK pathways (p38, ERK1/2, and JNK) and the repression of the plasminogen activator inhibitor. Overall, the levels of TNF-α, IL-1β, IL-6, and Th2 decreased, which further decreased the extracellular-signal-regulated kinase (ERK) and Mitogen-Activated Protein Kinase (MAPK) expression, and increased NK cell cytotoxicity [ 158 , 173 , 174 ]. Curcumin is a polyphenol present in turmeric. Curcumin has been used as a potent immunomodulatory agent in the last two decades and can modulate the activation of T cells, B cells, macrophages, neutrophils, natural killer cells, and dendritic cells [ [175] , [176] , [177] , [178] ]. Furthermore, it can also downregulate the expression of pro-inflammatory cytokines, including TNF, IL-1, IL-2, IL-6, IL-8, IL-12, and chemokines, probably through the inactivation of the transcription factor NF-κB [ 179 ]. Also, it induced the expression and production of IL-10 [ 180 ]. In Vero E6 infected with SARS-CoV-2 and in-silico analysis, curcumin was shown to inhibit the S glycoprotein and ACE2 receptor of SARS-CoV-2 with a docking score of −141.36 and −142.647 kcal/mol [ 103 ]. Furthermore, double-blind, randomized, controlled trial, was conducted in a dedicated COVID-19 Health Center where, 70 COVID-19 patients (treatment group) were co-administered with oral curcumin-piperine capsule and the other 70 COVID-19 patients (control group), received co-administration of probiotics and both groups received conventional COVID-19 treatment [ 181 ]. Here, it was observed that the treatment group had reduced symptoms such as fever, cough, sore throat, and breathlessness compared to the control group, and furthermore, the oxygen requirement as well as the need for remdesivir injections were reduced as was the need for mechanical ventilation. As such it has been suggested that the co-administration of piperine and curcumin can improve clinical outcomes in patients with COVID-19 especially weakness [ 181 ]. Resveratrol is a polyphenolic phytoalexin, present in berries such as cranberry, blueberry, and mulberry, among many. Its immunomodulatory activity was studied on splenic lymphocytes, peritoneal macrophages, EV71-infected RD cells, HTLV-1 infected cells, adipocytes, and rabbit model of acute pharyngitis and was found to cause irreversible inhibition of IFNγ and IL-2, a reduction of IL-1α, IL-6, IL-8, IL-12, and MCP1 levels, downregulating IL-17, inhibiting TNFα and also cause blocking of the NF-κB pathway while reducing the protein expression of IL-1β and IL-18 [ 7 ]. In live SARS-CoV-2 infected Vero cells, resveratrol significantly inhibited the replication of SARS-CoV-2 with an EC50 value of 4.48 μM [ 182 ]. Based on various literatures and molecular docking studies, in 2020, a phase 2 randomized double-blind placebo-controlled trial was conducted for proof of concept of resveratrol for the outpatient treatment of mild COVID-19 [ 183 ] and it was found that resveratrol has a potential biologic effect on the patients [ 184 , 185 ]. However, it is associated with poor bioavailability and the authors mention the utility of its metabolite, resveratrol-glucuronide, being more potent as seen from docking studies with SARS-CoV-2 [ 183 ]. A randomized double-blind placebo-controlled trial with resveratrol for outpatient treatment of mild COVID-19 was conducted in Central Ohio and outcomes demonstrated lower incidence of hospitalization and Pneumonia [ 186 ]. Oleuropein is a phenolic compound, present in fruit, leaves, and oil of olive [ 187 ]. In docking studies, oleuropein inhibited the NSP15 endoribonuclease activity of SARS-CoV-2 [ 188 ]. Its anti-inflammatory and antioxidant activity is well characterized. In a study conducted in rats, oleuropein was found to inhibit the activity of lipoxygenase and the production of leukotriene B4 [ 189 ]. Furthermore, it is not only a nitric oxide scavenger but can also increase the expression of inducible nitric oxide synthase (iNOS) in mouse macrophage cells. Its scavenging effect was studied against hypochlorous acid (HOCl), an endogenous oxidative substance produced in-vivo by neutrophil myeloperoxidase at the site of inflammation, that causes damage to the intracellular proteins, including enzymes [ 190 ]. Gingerol is a beta-hydroxy ketone found naturally in ginger ( Zingiber officinale ) and is often present in ginger as 6-gingerol, 8-gingerol and 10-gingerol, and when heated converts to Shogaol. Multiple studies were conducted to understand the antiviral activity of gingerol that includes hepatitis A & C, Tulane virus, influenza, human respiratory syncytial virus and many more [ 191 ]. It has been studied that its capacity to modulate the Th2 cell-mediated responses in animal models makes ginger a cheap and affordable remedy to manage the cytokine storm that occurs in COVID-19 patients. Gingerol is known to cause suppression of differentiation of Th cells and thereby, downregulating the production of cytokines, suppressing IgE production, and preventing the accumulation of mast cells in mouse models [ 192 , 193 ]. Furthermore, studies on LPS-stimulated macrophages and DSS-treated Caco-2 cells reveal that gingerol causes a reduction of pro-inflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-10, IL-12, Il-17, TNFα, and chemokine CXCL8, cause down-regulation of NF-κB pathway and AMPK activation [ 7 , [194] , [195] , [196] , [197] ]. Studies revealed that gingerol inhibited the SARS-CoV E protein [ 198 ]. In multiple docking study, the binding energy of 6-gingerol against SARS-CoV-2 spike protein was −38.60 kcal/mol, whereas the binding energy of 8-gingerol, 10-gingerol, 10-Shogaol against SARS-CoV-2 ACE-2 receptor was found to be −46.85, −33.72, −44.61 kcal/mol, respectively [ 199 ]. Furthermore, 6-gingerol was found to target multiple viral protease residues of 5R7Y, 5R80, 5R81, 5R83, 5R84 and 6LU7 with a docking score of −15.7591, 7.0885, 8.2021, −7.4778, −9.5168, −2.8764 kJ/mol, respectively [ 200 ]. In 2022, a randomized, double-blind, placebo-controlled clinical trial 2 [ 183 ] was conducted to investigate the safety and efficacy of BEJO Red Ginger in hospitalized adult COVID-19 patients with mild clinical manifestations as an adjuvant to standard therapy and the results are yet to be seen [ 201 ]. A clinical trial with normal-dose (3000 mg) and low-dose (1500 mg) ginger per day on 109 COVID-19 patients demonstrated that low-dose ginger reduced the percentage of patients with dehydration from 72% to 42% and severely infected COVID-19 patients had higher level of oxygen as compared to the control group [ 202 ]. However, no clinical trial on COVID-19 patients has been conducted with pure gingerol. Eugenol is present in nature in cinnamon bark, tulsi leaves, and turmeric, among many. It has been studied on LPS-induced macrophages and LPS-activated cells, mouse peritoneal macrophages, and male Wistar rats [ 7 , 203 ]. Isolated eugenol suppressed COX-2 genes in the HT-29 human colon cancer cell line and exhibited inhibition of PGE-2 considerably, having an IC 50 value of 0.37 μM [ 204 ]. They also revealed that eugenol inhibited the propagation of HT-29 cells and the mRNA expression of the COX-2 gene [ 7 , 204 ]. Furthermore, eugenol operates via the reduction of IL-1β, IL-4, IL-5, IL-6, and IL-10 levels, downregulation of pro-inflammatory cytokines IL-6 and TNFα, and inhibition of NF-κB, ERK1/2, and p38 MAPK signaling pathways. In multiple docking studies, the binding energy of eugenol with SARS-CoV-2 E (envelope) protein, M (membrane) protein, S (spike) protein and ACE-2 receptor was found to be −17.87, −24.58, −22.04 and −26.87 kcal/mol, respectively, which demonstrated eugenol's ability to prevent viral entry into the host [ 205 ]. Furthermore, in the same study, the authors conducted in-vivo tests on hamster models by dividing the group into 5, Group 1: Control (n = 3); Group 2: Infected (n = 5); Group 3: Infected + Remdesivir (n = 5); Group 4: Infected + FEO (n = 5) and Group 5: Prophylactic FEO + Infected (n = 5). It was found that the lung injury score was reduced in FEO treated and pretreated groups, thereby indicating the ability of the essential oil to prevent viral entry into lung cells [ 206 ]. Therefore, further tests need to be done to determine its effect on COVID-19 patients. Astaxanthin obtained from Haematococcus pluvialis has shown the capacity to induce proliferation of splenic lymphocytes significantly, enhance the IL-2 and INF-γ production, in addition to inhibiting the MAPK and NF-κB cell signaling pathway while reducing the IL-6, IL-1bTNF-α level, as observed in cultured lymphocytes, mice as well as human [ 206 ]. In-silico docking study revealed the binding affinity of astaxanthin with SARS-CoV-2 PLpro with a binding energy of −9.3 kcal/mol [ 207 ]. However, further studies are required to study their efficacy in-vivo and clinically . Andrographolide is a labdane diterpenoid found in Andrographis paniculata , and in docking studies, it was found to inhibit the main protease enzyme of SARS-CoV-2 with a binding energy of −3.094 kcal/mol [ 208 ]. In LPS/IL-4-activated murine macrophages, ischemic brain tissue, and LPS-stimulated RAW264.7 cells, it was found to reduce the levels of inflammatory cytokines (TNFα, IL-2, IL-12, IL-1β, IL-6, IL-18, INFγ) and suppress the inflammatory mediators (IL-1β, TNFα, PGE2, NOX2, iNOS) [ 90 , 209 ]. Furthermore, it causes suppression of NF-κB and MAPK pathways. It causes inhibition of TNFα/NF-κB and TLR4/NF-κ signaling pathways while decreasing the ERK1 and ERK5 phosphorylation induced by anti-CD3 or PMA/ionomycin [ 90 , 208 , 209 ]. Currently, a phase 3 randomized controlled trial 2 [ 183 ] of Andrographis paniculata extract, Boesenbergia rotunda extract, and standard treatment in 3060 asymptomatic COVID-19 patients is ongoing which would assist to help us understand the clinical outcome of administering andrographolide [ 210 ]. Floralginsenoside B is a triterpene saponin found in Panax ginseng (including Rb1, Rb2, Rc, Rd, Re, Rf, Rg1, Rg3, and Rh1). In U937 cells, ginsenosides significantly inhibit TNFα-induced CXCL-10 expression, and the CXCL-10 suppression can be correlated with the inactivation of ERK1/2 pathways [ 211 ]. Rb2 strongly blocked Con A, LPS, and PHA-induced lymphocyte proliferation. Moreover, Rb2 inhibited Con A-stimulated IL-2 production. In the IL-2-stimulated CD8 + T cell (CTLL-2) proliferation assay, Re and Rg1 showed strong suppressive effects [ 211 , 212 ]. In a molecular docking study, seven compounds from Panax ginseng were used and it was found that Floral Ginsenoside B showed a strong binding affinity of −8.618 kcal/mol with the receptor-binding domain (RBD) of SARS-CoV-2 [ 212 ]. Glycyrrhizin is also a triterpenoid found in the roots of Licorice radiata . In mice models, it was seen to enhance the proliferation of T-helper lymphocytes while promoting IL-2, INF-γ, IL-1, and other cytokines in addition to inhibiting IL-4, IL-10 and IL-8 [ 206 , 213 ] It was further shown to have an IC 50 value of 316–625 mg/L [ 214 , 234 ]. And in the docking studies, it inhibited the SARS-CoV-2 Mpro and RdRp with binding energies of −3.41 and −7.77 kcal/mol, respectively [ 215 , 216 ]. Morphine is an opiate alkaloid obtained from the poppy seeds of P. somniferum . The chemical constituents of morphine bind to the δ, μ, κ opiate receptors which activate and control several brain functions [ 7 ]. It is used for analgesic, and sedative action and causes pulmonary depression and smooth muscle contraction in the gastrointestinal system [ 217 ]. It is known for the immunosuppressant activity for many years and has been established in several studies in recent years. The mechanism of action of its immunosuppressant activity mainly involves inhibition of the cytokine production [ 7 ]. Studies showed that morphine causes a reduction of TNFα, IFNγ, MCP 1, IL-1, IL-2, IL-12, IL-6 and MIP2, and inhibition of transcription factor NF-κB in multiple animal models Swiss-Webster and CB6F1 male mice, C57BL/6 J rats as well as in the lung resident cells of mice [ 218 ]. A study on mast cells of mice to observe the intraperitoneal release of TNFα and MCP 1 showed the effect of morphine in the reduction of LPS-induced TNFα but a non-significant effect for MCP1 release [ 219 ]. Docking studies revealed high binding affinity of morphine towards the SARS-CoV ACE receptor show promise for its inhibitory action on the receptor mediated cytokine release [ 7 ]. Therefore, the immunosuppressant activity of morphine makes this compound an ideal candidate for reduction and inhibition of cytokine storm in COVID-19 infection. Combination of morphine, remdesivir and dexamethasone treatment surprisingly eliminated hypoxaemia and dyspnoea in a severely ill hospitalized COVID-19 patient and improved the condition of this patient [ 220 ]. However, morphine did not show any significant changes in COVID-19 patients during clinical trials with this compound [ 221 ]. Considering a few limitations on the timing of morphine administration this natural compound can be explored to modify its action in the treatment of COVID-19. Ursolic acid is a triterpenoid found in many herbs and spices. In docking studies, ursolic acid from Ocimum sanctum (holy basil) showed high binding energies of −8.7 kcal/mol with the Mpro of SARS-CoV-2, thereby, blocking the Mpro enzyme of the virus [ 172 ]. Its role as an immunosuppressant has also been studied in in-vitro models -immune cells and Mono Mac 6 [ 54 , 206 , 222 , 223 ]]. Ursolic acid accelerates the production of interleukin IL-10, IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-β while reducing the expression of IL-1β, IL-6, TNF-α, and transforming growth factor-beta 1 (TGF-β1) [ 224 ]. Its effect has not yet been studied in clinical trials, but it is listed as a potential drug candidate to mitigate post-COVID-19 complications such as lung fibrosis due to its ability to attenuate anti-inflammatory reactions and oxidative stress [ 225 ]. Allicin is a thiosulphate found naturally in garlic, Allium sativum , and is known for its virucidal activity against herpes simplex virus type 1 & 2, parainfluenza virus type 3, vesicular stomatitis virus, and human rhinovirus type 2 [ 226 ]. To determine the immunomodulatory activity of allicin, in-vitro studies-intestinal epithelial cells, HT-29, and Caco-2 cells-were conducted by Grigore (2017) [ 90 ]. Allicin showed a reduction of IL-1β, CXCL8, and IP10 levels and an increase of CD4 + T-cells. Furthermore, it led to inhibition in the secretion of IL-1β, IP10, CXCL8, and MIG [ 90 ]. In multiple docking studies, allicin was shown to inhibit the SARS-CoV-2 Mpro with a binding energy of −3.6 kcal/mol [ 172 ]. Cordifolioside belongs to a group of compounds called a phenylpropene disaccharide and is the other bioactive found in T. cordifolia . Multiple docking studies reveal that cordifolioside is an inhibitor against the Mpro of SARS-CoV-2 with docking scores and binding energies of −7 and −21.04 kcal/mol, respectively, which can act as a vital immunomodulator on human TGF-β and TNF-α [ 105 ]. Therefore, in a separate docking study involving biomarkers TGF-β and TNF-α, interactions and binding energies of cordifolioside, magnoflorine and berberine were studied and cardiofolioside was found to be the most attractive of the three with the lowest binding energy and highest conformational stability [ 105 ]. Therefore, cordifolioside has been suggested as an attractive drug to determine its role in patient outcomes and by studying the underlying mechanism of TGF-β and TNF-α in COVID-19 patients can help in improving patient treatments. Melatonin is a natural product found in diets such as in a variety of herbs, black pepper, nuts, beans, rice and seeds. Beyond sleep regulation, in mammals, it is responsible for a wide variety of immunomodulatory functions. It is produced by the pineal gland well as by the human lung macrophages; hence, when COVID-19 affects the lung macrophages, mitochondria is unable to synthesize melatonin, thus, unable to fight the inflammation or neutralize the reactive oxygen species in the lungs [ 227 ]. Mechanistic study in immune cells of COVID-19 patients showed that melatonin is responsible for the inhibition of NLRP3 inflammasome activation as well as inhibition of MCP1, CCL5 and CCL9 mRNA expression, by reversing aerobic glycolysis to produce acetyl coenzyme A and downregulate the cytokine storm in COVID-19 [ 7 , 228 ]. A phase 2 single-blind, randomized, placebo controlled clinical trial (Eudract: 2020‐001808‐42) was conducted to explore the effectiveness and safety of intravenous administration of melatonin in COVID-19 patients entering ICU [ 229 ]. In this study, 12 subjects were treated with melatonin and 6 with placebo, and it was found that a significantly large number of deaths occurred in the melatonin group (5 people in the melatonin treated group, 1 person in placebo group). In multiple other clinical trials where melatonin was given orally, the results while decreasing mortality, the results were not statistically significant [ 230 , 231 ]. Thus, it can be concluded that while IV administration of melatonin for critically ill patients may be fatal, the oral administration of melatonin at the early stages of COVID-19 infection can help [ 239 ]. Withanone , obtained from Withania somnifera , belongs to a group of compounds called steroidal lactones. Extract from W somnifera are used by African tribes to treat genital infection [ 232 ]. On BALB/c mice, withanone leaf extract showed immunomodulatory activities, enhancing Th1 cytokine IFN-γ expression in Con A primed splenocytes in-vitro . Moreover, it caused the dose-dependent growth of T cells and improved their ability to secrete IL-2 and IFN-γ [ 233 ]. However, it moderately down-regulated Th2 cytokine IL-4. Furthermore, the flow cytometric analysis of lymphocyte surface markers of T cells CD3 + , CD4 + and CD8 + , and B cells CD19 + indicated significant enhancement in proliferation and differentiation of lymphocytes [ 233 ]. In docking studies with SARS-CoV-2 ACE2-RBD complex, withanone showed significant interruption of electrostatic interactions by binding with a binding energy of −9.4 kcal/mol, thereby blocking or weakening COVID-19 entry [ 206 ]. In a separate study, withanone was seen to bind to the Mpro of SARS-CoV-2 with a binding energy of −4.42 kcal/mol, thereby interrupting viral entry into the host cell [ 234 ]. Its effect was studied with zebra fish infected with SARS-CoV-2 spike protein and treatment of fever with either dexamethasone or withanone [ 235 ]. It was found that for both the treated groups on day 6 of the treatment, fever was reduced, thus, showing the adaptive immune response against the virus. No clinical study has yet been done.

After the devastating and wide-spreading COVID-19 situation, it is urgent to find and develop a novel therapeutic agent for treating COVID-19 and its new variants-induced infection. Only the vaccine rollout is not enough to eradicate the disease worldwide. Re-purposing the existing immunomodulatory drug could be a strategy in drug discovery [ 73 ]. Moreover, an alternative will be a new lead compound with an immunomodulatory action isolated from the natural plant source. The immunomodulatory activity of the drug is the reorganizing of the inflammatory response by modifying the functions of the immune system [ 74 ]. Its mechanism of action varies, and they can be broadly categorized as either. ● immunostimulants: drugs that enhance the immune system ● immunosuppressants: drugs that suppress the immune system immunostimulants: drugs that enhance the immune system immunosuppressants: drugs that suppress the immune system When the SARS-CoV-2 virus infects a person, the disease-causing pathogen stimulates the release of pro-inflammatory cytokines, for example, IL-1β and IL-6, which are responsible for the cytokine storm in the body liable for acute respiratory distress syndrome, organ damage, multiple organ failures, and eventually death [ 75 ]. If cytokine release can be stopped or prevented at the early stage of the disease, the patient can be saved. This strategy was applied in the management of disease progression as identified by the American College of Rheumatology, which ascertains the continuation of hydroxychloroquine/chloroquine treatment with or without COVID-19 infection, because of the increased risk of disease flare in rheumatoid patients due to discontinuation of immunosuppressants [ 76 ]. Thus, preventing/managing the exponential growth of inflammation at the early stage of the infection would be beneficial. This suppression can be done with an immunomodulatory therapeutic agent called an IL-6 receptor antagonist, and in this pathway, the immunomodulatory action is obtained by normalizing the inflammatory markers in the serum [ 77 ]. That is why immunomodulatory drugs were recommended in the management of COVID-19 infection [ 78 , 79 ]. Type 1 interferons with immunomodulatory properties are also candidates for treatment during the early stage of this disease since they prevent viral attacks of host cells [ 80 , 81 ]. Immunomodulatory effects include activation of macrophages, natural killer cells, and T-cell, T-cell clonal proliferation, and CD4 + and CD8 + T-cell stimulation [ 82 ]. Two important Janus kinase (JAK) inhibitors namely, baricitinib and tofacitinib have been recommended for COVID-19 treatment due to their potential of stopping signal transduction leading to immune activation and systemic inflammation. Clinical trials with baricitinib plus remdesivir demonstrated quicker patient recovery (7 days) from COVID-19 infection compared to the control group who were administered a placebo (8 days). In another clinical trial with tofacitinib, after 4 weeks the incidence of death or respiratory failure was 18.1% in the tofacitinib-treated group whereas this incidence was 29% in the placebo-treated group [ 83 ]. Tocilizumab, an FDA-approved recombinant humanized anti -IL 6 receptor monoclonal antibody (mAb), is used for the disease syndrome where cytokine release is involved [ 78 ]. It is now evident that the levels of IL-1, IL-6, and TNF alpha cytokines are found to be increased with SARS-CoV-2 infection [ 79 ]. Systemic inflammation in the COVID-19 patients was associated with elevated IL-6 levels and Tocilizumab has been suggested for the severely infected COVID-19 patients [ 83 ]. Tocilizumab inhibits IL-6 signal transduction pathways by binding with soluble and membrane-bound IL-6 receptors, thus, reducing the levels of IL-6 in COVID-19 patients [ 84 ]. Based on the clinical outcomes of a randomized trial Tocilizumab in conjunction with dexamethasone is now used for the treatment of COVID-19 patients who demand oxygen supply, and non-invasive or invasive mechanical ventilation [ 83 ]. Corticosteroids have been reported to inhibit lung inflammation in severely infected COVID-19 patients thus repressing inflammation-induced lung injury. A daily dose of 6 mg dexamethasone decreased the 28-day mortality rate for COVID-19 patients requiring invasive mechanical ventilation or oxygen therapy [ 85 ]. There are several mechanisms through which Dexamethasone (DXM) can induce anti-inflammatory action against invading pathogens. The most prominent one is by restraining AP-1 and NFκB transcription factors. Upon binding with GR (Glucocorticoid receptor), DXM relocates to the nucleus and exerts its activity, and this DXM-GR can interact with c -jun and then repress AP-1. Interaction of DXM-GR with p65 and p53 can inhibit NFκB activity. DXM-GR can prevent the NFκB/IRF3 (interferon regulatory factor 3) heterodimer formation by recruiting GRIP (GR interacting protein). The activity of NFκB can also be inhibited by not letting NFκB interact with p300 and CBP (CREB1-binding protein) [ 86 ].

Plant-derived compounds that demonstrated promising immunosuppressant activity have been categorized based on their class ( Table 2 ): Below is a detailed discussion on each class of natural compounds with immunosuppressant action. Table 2 List of natural immunomodulators not yet studied against SARS-CoV-2. Table 2 Class Compound Source Mechanism of immunomodulatory action IC 50 Studied models References Alkaloid Nicotine Tobacco Suppression of TNF, IL-1, IL-2, Il-6, IFNγ, TNFα, IL-1β and MIP1 level; Inhibition of NF-κB; Activation of JAK2 and STAT3 – Human macrophages and splenocytes; PBMC [ 7 , 240 , 241 ] Opiate alkaloid Codeine Poppy seeds (P. somniferum) Inhibits cytokine release by binding to SARS-CoV-2 ACE receptors – Swiss–Webster, C57BL/6 J rats, CB6F1 male mice; lung resident cells; male Swiss mice; docking study against ACE receptor [ 7 ] Glycoside Scrocaffeside A Picrorhiza scrophulariiflora Enhanced proliferation of splenocytes and their response to polyclonal T cell mitogen concanavalin A (Con A) and lipopolysaccharide (LPS); The production of cytokines and the CD4/CD8 population of splenocytes were also elevated; increased levels of interleukin (IL)-2, IL-4, IL-12, and (IFN)-gamma expression – BALB/c male mice [ 249 , 250 ] Oxygenated lignans Arisantetralones A-D (1–4) and arisanschinins F-L (5−11) Schisandra arisanensis The immunomodulatory effect of compound 4 on human peripheral blood mononuclear cells (PBMC) proliferation was better than the others. In addition, compound 5 exhibited cytotoxicity against HEp-2, Daoy, MCF-7, and WiDr tumor cell lines with ED50 values of 4.12, 6.23, 4.09, and 6.08 μg/mL, respectively. Compound 5's ED50 values against HEp-2, tumor cell lines was 4.12 μg/mL PBMC [ 252 ] Phenolic compound Gallic acid Found in abundance in plants; in the bark, wood, leaf, fruit, root, and seeds. Suppression of pro-inflammatory cytokines IL-1, IL-1β, IL-4, IL-5, IL-6, IL-12, IL-17, IL-23, TGFβ, TNFα and chemokines CCL2 and CCL7 level; Inhibition of NF-κB pathways; – Anti-CD3-stimulated spleen cells; Human monocytes; [ 7 , 248 ] Polysaccharide Fucoidan Brown seaweeds and some marine invertebrates Down-regulation of MAPK and NF-κB signaling pathways; Reduction of IL-6, IL-1β, Il-8, TNF-α expression, Up-regulation of INF-γ, IL-10, Reduction of iNOS, NO, PGE2, COX-2 level. Attenuation of CD86 expression. LPS-stimulated RAW 264.7 macrophages: 27.82 μg/mL; human recombinant COX-1: (IC 50 27 μg/mL); COX-2 (IC 50 4.3 μg/mL) LPS-stimulated RAW 264.7 cells; Human Keratinocyte Cell Line (HaCaT); Rat primary microglia; Caco-2 Cell Line and Caco-2/RAW 264.7 Coculture; Rodents, Mice, Zebrafish embryos, Rats, Murine paw edema. [ 251 ] List of natural immunomodulators not yet studied against SARS-CoV-2. Nicotine is an alkaloid present in tobacco plants scientifically known as Nicotiana Tabacum L. It is used as immunomodulator in peripheral nervous system and psychotropic disorders and to treat ulcerative colitis for its inflammatory effects [ 240 ]. Nicotine activates the a7-nicotinic acetylcholine receptor (a7-nAChRs) that induces the cholinergic anti-inflammatory pathway acting as a cholinergic agonist. The activation of a7-nAChRs in the macrophages and neutrophils causes the inhibition of NF-κB pathway which eventually constrains the secretion of pro-inflammatory cytokines and chemokines from these cells. The mechanism of immunomodulatory action of nicotine was seen via the suppression of TNF, IL-1, IL-2, Il-6, IFNγ, TNFα, IL-1β, and MIP1 level and inhibition of the NF-κB pathway in human macrophages and splenocytes. Nicotine suppresses the phosphorylation of I-κB that causes the loss of transcriptional activity of the NF-κB pathway resulting in its inhibition. It is also found to be responsible for the inhibition of LPS-induced TNFα secretion from human macrophages and splenocyte cells. These inhibitory actions of nicotine enable the activation of tristetraprolin (TTP) expression-mediated JAK2 and STAT3 pathways in macrophages. The function of nicotine as an anti-inflammatory agent has been studied on human macrophages, splenocytes, and peripheral blood mononuclear cells (PBMC) [ 7 , 240 , 241 ]. However, the suppression effect of nicotine on cytokine secretion was limited in RKO colon carcinoma-induced PBMC cells [ 241 ]. It remains a potential drug to explore in its role against SARS-COV-2, despite its notorious role in causing nicotine dependency and addiction. Codeine is an opiate alkaloid obtained from the poppy seeds of P. somniferum . It is a phenanthrene alkaloid obtained from a similar natural source as morphine. It is known to have analgesic, anti-diarrhoeal, and antitussive effects as an opioid agonist [ 217 ] It was observed that codeine treatment in the concanavalin A (ConA)-stimulated splenocytes of Swiss mice inhibits the production of IL-2 significantly [ 242 ]. Docking studies revealed high binding affinity of codeine towards the SARS-CoV ACE receptor show promise for its inhibitory action on the receptor mediated cytokine release [ 7 ]. Therefore, the immunosuppressant activity of codeine makes it an ideal candidate for reduction and inhibition of cytokine storm in COVID-19 infection. However, no studies have yet been conducted to observe the direct effect of codeine on SARS-CoV-2. Considering certain cases of cytokine and chemokine induction by codeine, this natural compound can be explored to modify its action in the treatment of COVID-19. Gallic acid is a phenolic compound, found in many plants' bark, wood, leaf, fruit, root, and seeds. It is used as an antioxidant with anticancer, antifungal, antimicrobial and anti-inflammatory effects. The anti-inflammatory activity observed in TNBS-induced ulcerative colitis by inhibition of the pro-inflammatory cytokines IL-1, IL-1β, IL-4, IL-5, IL-6, IL-12, IL-17, IL-23, TGFβ, and TNFα, and chemokines CCL2 and CCL7 and blocking the NF-κB pathway [ 243 ] s. Kim et al., 2006 found similar effects of gallic acid when treated on human mast cells (HMC-1) to block the secretion of TNFα and IL-6 [ 244 ]. The selective effect of gallic acid was revealed in a study on anti-CD3-stimulated spleen cells where Th2 cytokines IL-4 and IL-5 were inhibited but not Th1 cytokines IFNγ [ 245 ]. NF-κB expression was significantly decreased in the LPS-induced endometriosis cells treated with gallic acid by the inhibiton of phorbol myristate acetate (PMA) plus A23187-induced IκBα degradation and p65 NF-κB nuclear translocation. This inhibition results in the suppression of the pro-inflammatory cytokine IL-6 exerting the anti-inflammatory effect of gallic acid [ 246 ]. Moreover, progallic acid produced by the enzymatic breakdown of gallic acid also decreases the production of IL-6, TNFα and IL-1β cytokines in the PMA induced human monocyte [ 247 ]. Gallic acid can selectively suppress the pro-inflammatory cytokines without interfering with the desired interferon production in COVID-19 patients. These characteristics make gallic acid an ideal candidate for the immunosuppressive activity to combat the cytokine storm caused by COVID-19 infection [ 7 , 248 ]. Scrocaffeside A is a glycoside found to occur in nature in Picrorhiza scrophulariiflora. As a herb this medicinal plant was found to be used for several diseases like tumors and liver infections. Here, scrocaffeside A is collected from the methanol extract of the plant to investigate its potential as an immunomodulator. An et al. (2009) and later, Singh et al. (2016) studied its effect on the BALB/c male mice model [ 249 ]. They found that Scrocaffeside A enhanced the proliferation of splenocytes and their response to polyclonal T cell mitogen concanavalin A (Con A) and lipopolysaccharide (LPS) in addition to increasing the production of cytokines and the CD4/CD8 population of splenocytes. A dose-dependent increase in the activity of macrophages and the natural killer cells was observed when treated with 5–125 μg/mL dose of scrocaffeside A and a similar pattern was seen in case of mature T-cell subsets. It was seen that there were increased levels of interleukin (IL)-2, IL-4, IL-12, and (IFN)-gamma expression within the male mice [ 249 , 250 ]. Hence, these effects of scrocaffeside A demonstrated its prospect for the immunostimulation properties which should be explored for the treatment of COVID-19 infection. Fucoidan is a polysaccharide present in brown seaweeds and some marine invertebrates. This compound has been proposed for biological applications in cancer, diabetes, colitis, pancreatitis, gout, infections, neurodegenerative diseases and stem cell therapy etc. The mechanism of action of fucoidan to exert anti-inflammatory effects is reported to involve blocking the adhesion and invasion of lymphocytes, inactivation of the enzymatic functions and initiation of apoptosis [ 251 ]. Several in-vivo and in-vitro studies were conducted by Apostolova et al. (2020) to determine the extent of its immunomodulatory activity, namely on LPS-stimulated RAW 264.7 cells, human keratinocyte cell line (HaCaT), rat primary microglia, Caco-2 cell line, and Caco-2/RAW 264.7 coculture, rodents, mice, rats, zebrafish embryos and murine paw edema [ 251 ]. In these studies, it was observed that fucoidan caused down-regulation of MAPK and NF-κB signaling pathways in addition to causing a reduction of IL-6, IL-1β, Il-8, TNF-α expression, and iNOS, NO, PGE2, COX-2 level while an up-regulation of IFN-γ and IL-10. In addition to these, it was found to attenuate CD86 expression. The LPS-stimulated RAW 264.7 macrophages yielded an IC 50 value of 27.82 μg/mL, while its inhibition of human recombinant cyclooxygenase COX-1, and COX-2, yielded an IC 50 value of 27 and 4.3 μg/mL, respectively [ 251 ]. While its effect on the COX-2 pathway was prominent, fucoidan remains a potential immunomodulatory suppressant, and its inhibitory effect on the SARS-CoV-2 is yet to be determined. Arisantetralones A-D (1 – 4) and arisanschinins F-L belong to the class of oxygenated lignans present in Schisandra arisanensis. The fruit extract of S. arisanensis was used to isolate eleven new oxygenated lignans (compound 1–11) namely arisantetralones A-D (compound 1–4) and arisanschinins F-L (compund 5–11) and evaluate their effects in inhibition of peripheral blood mononuclear cells (PBMC) induced by phytohemaglutinin (PHA). All the isolated compounds were tested in-vitro by using 100 μM dose of each compound (1−11) in the resting cells and PBMC induced by PHA at the concentration of 0.2 μg/mL and 5 μg/mL. According to Cheng et al. (2009), the immunomodulatory effect of Arisantetralone D (compound 4) on human PBMC proliferation was better than the others. In addition, Arisanschinin F (compound 5) exhibited cytotoxicity against HEp-2, Daoy, MCF-7, and WiDr tumor cell lines with ED50 values of 4.12, 6.23, 4.09, and 6.08 μg/mL, respectively [ 252 ]. These isolated new compounds have not been investigated further in-vivo for their immunomodulation action. Hence, more studies need to be performed to investigate the inhibitory activity of compounds 4 and 5 against SARS-CoV-2.

COVID-19 and its several new variants induced immune-inflammatory cascade-responses are responsible for the pathogenesis and complications in covid patients. Severe consequences are evident in people with dysfunctional and compromised immune systems. To date, no specific, accurate, and effective drugs are available to treat SARS-CoV-2 induced infection. However, some non-selective antiviral, immune modulators, antiparasitic, antimalarial, antiviral, antibacterial, corticosteroids, and anticoagulant drugs have been used to treat COVID-19 infection as well as few vaccines are in use globally to prevent this deadly virus with uncertainty to what extent they will give protection or will be effective against SARS-CoV-2 new variants. Hence, extensive research is warranted on finding new, safe, and effective molecules to treat this infection and to reduce COVID-19-related mortality and morbidity. Natural products are well-reported for their immunomodulatory potential, and several natural immunomodulators have already been tested against COVID-19 and exhibited promising results. Thus, there is an urgent need to screen and validate all possible natural immunomodulators and their molecular mechanisms using in-silico , in-vitro , in-vivo methods, preclinical and clinical trials to discover new selective and effective anti -SARS-CoV-2 drugs. Designing future therapeutic agents targeting immunomodulatory pathways with natural products would be highly intriguing.

Current and relevant data were extracted on the selected topic by an extensive search using the following databases: Google Scholar, PubMed, Springer, Science Direct, MedLine, Scopus, Web of Science, and the Website of WHO. The keyword ‘COVID-19/coronavirus' was paired with ‘natural immunomodulators' ‘natural products', ‘natural bioactive compounds' ‘herbal drugs', 'phytochemicals', 'alkaloids', 'glycosides', 'flavonoids', 'saponins', 'terpenes', 'terpenoids', tannins', 'phenols', 'polyphenols' to obtain published data till February 2022. Gathered information in this review was included based on these criteria; i. Studies involved immunomodulatory effects of natural products ii. Studies conducted on derivatives of natural products (e.g., isolated compounds) and/or chemicals or biochemicals for their immunomodulatory/immunosuppressive/anti-inflammatory potential.

Since the first emergence of the coronavirus disease 2019 (COVID-19) in Wuhan, China, it has spread alarmingly across the world. The World Health Organization (WHO) declared COVID-19 as a public health emergency on January 30, 2020, and on March 11, 2020, WHO announced it as a global pandemic [ 1 ]. To date, more than 71 million confirmed cases with more than 1.6 million death tolls have been reported by the WHO [ 2 ]. COVID-19 is caused by the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the seventh known virus of the Coronaviridae family [ 3 ]. Human to human transmission of coronavirus occurs by close contact with the infected individuals through respiratory droplets either from sneezing or coughing, physical contact, and aerosol transmission. COVID-19 infected patients show various unspecific symptoms, such as fever, cough, myalgia or fatigue, headache, less frequent gastrointestinal diseases, and severe progressive respiratory failure in extreme cases [ 4 , 5 ]. Immunocompromised people with comorbidity and low immunity who are suffering from various infectious and noninfectious diseases have been reported to be affected largely by the COVID-19 [ 6 ]. The complex immune dysfunction observed in COVID-19 patients causes deleterious clinical manifestations leading to organ injury, subsequent organ failure, and ultimately mortality. In COVID-19 patients, the hallmark of immune dysregulation is observed as a cytokine storm manifested as hypercytokinemia and hyperinflammation [ 7 ]. In addition to hypercytokinemia, neutrophilia, persistent lymphopenia, over-activation of complement components C3, C3a, C5, C5a, and mannose-binding lectin-associated serine protease (MASP2) are the factors contributing to hyperinflammation [ 8 ]. In severely ill COVID-19 patients, elevated levels of several pro-inflammatory cytokines including G-CSF, IP-10, MCP-1, MIP-1a, IL-2, IL-6, IL-7, IL-10, and TNF- α have been determined in the blood after being infected with the coronavirus. These indicate the association between severe clinical manifestations of COVID-19 patients with cytokines [ 3 , 9 ]. Substantially lower lymphocyte count and reduced CD4+T-cells, CD8+T-cells, and natural killer cells were evident in COVID-19 patients with severe pneumonia [ 10 , 11 ]. It has also been reported that SARS-CoV-2 disrupts normal immune responses of severely and critically infected COVID-19 patients, leading to impaired immune systems and uncontrolled inflammatory responses [ 12 ]. Severe patients with COVID-19 have been detected with lymphopenia, lymphocyte dysfunction, granulocyte and monocyte abnormalities, high cytokine levels, and increased immunoglobulin G (IgG) and total antibodies [ 12 ]. SARS-CoV-2 mediated immune responses caused multiple-organ failure (MOF), viral sepsis, lung injury leading to ARDS (acute respiratory distress syndrome), respiratory failure, shock, and potentially death in patients with severe COVID-19 infection [ 13 ]. Several studies reported a close correlation of the elevated cytokine level with severe syndromes of multiple organ failure; thus, modulation of the high cytokine level could be potentially used as a therapeutic or prophylactic target for severe syndromes in COVID-19 patients. The current scenario shows that patients with weak immunity are highly susceptible to COVID-19 infection and its severe consequences. In this context, natural compounds with immunomodulatory potential may be beneficial in fighting COVID-19 [ 7 ]. Since ancient times, phytocompounds have been used as life-saving drugs [ 14 ]. Historically natural products and their derivatives have made a major contribution to drug discovery and development, especially for infectious diseases and cancer [ 15 ]. Natural products and their structural derivatives constitute an extremely significant resource for therapeutics, for instance, they are used as direct therapeutic agents or provide a template for semisynthetic drugs, prototypes for new drug design, and taxonomic markers for new drug discovery [ 15 , 16 ]. Natural bioactive compounds with significant antiviral, anti-inflammatory and immunomodulatory activity have been used in many developing countries for COVID-19 treatment [ 17 ]. Although several medications have been used or are under trial to fight COVID-19 infection, no specific drugs for treating this infection are available to date. Therefore, there is an urgent need for selective and effective treatment modalities for treating COVID-19 infection. Several review articles have discussed the importance of medicinal plants/herbs and phytocompounds as a remedy for COVID-19 infection highlighting their antiviral potential. However, to the best of our knowledge, no review articles delineated the significance of natural compounds as immunomodulators to combat this infection [ 18 ]. Thus, this present review discusses the plausibility of natural compounds with immunomodulatory potential as therapeutic targets for COVID-19. Also, this study has compiled a list of natural immunomodulators that would serve as an important resource to the researchers to conduct further research on them in finding the best lead molecule for the development of immunomodulators against COVID-19 viral disease affecting the immune system.

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

Data included in article/supp. Material/referenced in article.

Immunopathological aspects of the SARS-CoV-2 virus involved impaired innate immune system, hyperinflammation [ 19 ], cytokine storm leading to acute respiratory distress syndrome and multiple organ failure [ 20 , 21 ]. It is also associated with lymphopenia due to decreased levels of T-cells, B-cells, eosinophils, neutrophils and other important immune cells taking part in the immune response [ 20 , 22 ]. The occurrence of autoimmune disorders due to the failure of the self-recognition mechanism of toll-like receptor-7 (TLR-7) causing the auto reaction [ 23 ] and post-acute sequelae of SARS-CoV-2 infection [ 24 ] were observed as a consequence of the immunopathogenesis of this virus. Fig. 1 presents the pathogenesis of SARS-CoV-2 virus and immunopathological aspects by COVID-19 infection. Fig. 1 SARS-CoV-2 pathogenesis and immunopathological aspects by COVID-19 infection. Fig. 1 SARS-CoV-2 pathogenesis and immunopathological aspects by COVID-19 infection. SARS-CoV-2 virus binds to the ACE-2 receptor using the spike protein S and enters the endothelial cells of the respiratory tract through endocytosis [ 25 ]. The immune response is supposed to be initiated by recognizing the pathogen-associated molecular patterns of the SARS-CoV-2 virus by the toll-like receptors (TLRs) [ 26 ]. Thus the intracellular signaling process activating nuclear factors kappa-B (NF-κB) and interferon regulatory factors will result in the production of type I interferons (IFN I) and the pro-inflammatory cytokines. However, multiple proteins like open reading frame 6 (ORF6) and ORF3b in the SARS-CoV-2 virus inhibit the IFN I production and the signaling process to stimulate the initial immune response [ 27 ]. This inhibition of IFN I production allows viral proliferation and replication without an antiviral immune response leading to severe infection in the host. The infected tissue and cells trigger the elevated production of IFN I and IFN III and exacerbate hyper inflammation resulting in the severe progression of the disease [ 28 ]. NF-κB pathway and NOD, LRR-, and pyrin domain-containing protein 3 (NLRP-3) inflammasome activation triggers the macrophages, dendritic cells, T-cells and neutrophils to release elevated levels of pro-inflammatory cytokines IL-1, IL-2, IL-6, TNF-α and IFN-γ [ 29 ]. The central nervous system (CNS) is affected by the cytokine storm due to the leakage in the blood-brain barrier (BBB), and the microglial and IL-1 activation result in the neuroinflammation due to the increased production of reactive oxygen species (ROS), apoptosis, and cytokine expression. The CNS cytokine network and the immune system cytokine network influence each other through the neuropeptidergic pathway activated by regulating T-cells, phagocytosis, chemotaxis of neutrophils and mast cell activation [ 21 ]. Therefore, the inflammatory cytokines are transported to blood by overlapping CNS and immune system cytokine storms, causing the immune hijack. Thus, the dysregulated cytokine production causes healthy tissue damage, triggers the destruction of lymphocytes, causes lymphopenia and leads to multiple-organ failure (MOF), starting with lung damage and spreading to other organs like the heart, kidney, blood vessels and brain [ 21 ]. Lymphopenia has been considered one of the conditions as an immunopathological biomarker for the severe damage by SARS-CoV-2 infection. This condition is associated with decreased levels of total lymphocytes, including the CD4 + and CD8 + T-cells, B-cells and the natural killer (NK) cells in patients [ 30 ]. The activation of IFN-I, IL-2, IL-7 and the programmed cell death protein one and apoptosis was found to be responsible for the destruction of lymphocytes in the severely infected patients. Apart from these, suppression of bone marrow production due to cytokine storm, sequestration of lungs during pneumonia and heavy viral load also influence lymphopenia [ 31 ]. Autoimmunity and autoinflammation represent potential immunopathological conditions in SARS-CoV-2 infected patients, which may lead to post-acute sequelae infection termed long COVID [ 23 , 24 ]. Production of antiphospholipid (aPS) in severe COVID-19 infection activates the NF- κB pathway resulting in overexpression of TLR-7 and overactivation of pro-inflammatory cytokine response, which causes the failure of the self-recognition mechanism of TLR-7 [ 32 ]. Moreover, among critically ill COVID-19 patients, extrafollicular B-cells produce autoreactive antibodies, as seen in autoimmune disease settings. Such autoreactive antibodies show a high risk of initiating the post-acute sequelae of SARS-CoV-2 infection among critically ill COVID-19 patients [ 33 ]. In summary, the complex immunopathological effects of SARS-CoV-2 can vary widely between individuals. Advanced research is needed to thoroughly understand the mechanisms behind these effects and develop effective treatments for COVID-19.