Red Blood Cell DNA Capture and Delivery Drives Host Responses During Polymicrobial Sepsis

Red Blood Cell DNA Capture and Delivery Drives Host Responses During Polymicrobial Sepsis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Letter Red Blood Cell DNA Capture and Delivery Drives Host Responses During Polymicrobial Sepsis Long Kwan Lam, Nathan Klingensmith, Layal Sayegh, Emily Oatman, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2592196/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Red blood cells (RBCs), traditionally recognized for their role in transporting oxygen, play a pivotal role in the body's immune response by expressing TLR9 and scavenging excess host cell-free DNA. DNA capture by RBCs leads to accelerated RBC clearance and triggers inflammation. Whether RBCs can also acquire microbial DNA during infections is unknown. Murine RBCs acquire microbial DNA in vitro and bacterial-DNA-induced macrophage activation was augmented by WT but not TLR9-deleted RBCs. In a mouse model of polymicrobial sepsis, RBC-bound bacterial DNA was elevated in WT but not in erythroid TLR9-deleted mice. Plasma cytokine analysis revealed distinct sepsis endotypes, characterized by persistent hypothermia and hyperinflammation in the most severely affected subjects. RBC-TLR9 deletion attenuated plasma and tissue IL-6 production in the most severe endotype. Parallel findings in human subjects confirmed that RBCs from septic patients harbored more bacterial DNA compared to healthy individuals. Further analysis through 16S sequencing of RBC-bound DNA illustrated distinct microbial communities, with RBC-bound DNA composition correlating with plasma IL-6 in patients with sepsis. Collectively, these findings unveil RBCs as overlooked reservoirs and couriers of microbial DNA, capable of influencing host inflammatory responses in sepsis. Biological sciences/Immunology/Innate immunity/Pattern recognition receptors/Toll-like receptors Biological sciences/Microbiology/Microbial communities/Microbiome Health sciences/Medical research/Translational research Health sciences/Medical research/Experimental models of disease Biological sciences/Immunology/Infectious diseases/Bacterial infection Full Text Additional Declarations The authors declare no competing interests. Supplementary Files SupplementalInformation.pdf Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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DNA capture by RBCs leads to accelerated RBC clearance and triggers inflammation. Whether RBCs can also acquire microbial DNA during infections is unknown. Murine RBCs acquire microbial DNA in vitro and bacterial-DNA-induced macrophage activation was augmented by WT but not TLR9-deleted RBCs. \u0026nbsp;In a mouse model of polymicrobial sepsis, RBC-bound bacterial DNA was elevated in WT but not in erythroid TLR9-deleted mice. \u0026nbsp;Plasma cytokine analysis revealed distinct sepsis endotypes, characterized by persistent hypothermia and hyperinflammation in the most severely affected subjects. RBC-TLR9 deletion attenuated plasma and tissue IL-6 production in the most severe endotype. Parallel findings in human subjects confirmed that RBCs from septic patients harbored more bacterial DNA compared to healthy individuals. Further analysis through 16S sequencing of RBC-bound DNA illustrated distinct microbial communities, with RBC-bound DNA composition correlating with plasma IL-6 in patients with sepsis. Collectively, these findings unveil RBCs as overlooked reservoirs and couriers of microbial DNA, capable of influencing host inflammatory responses in sepsis.\u003c/p\u003e","manuscriptTitle":"Red Blood Cell DNA Capture and Delivery Drives Host Responses During Polymicrobial Sepsis","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2024-04-23 18:43:51","doi":"10.21203/rs.3.rs-2592196/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2023-04-04 02:40:50","doi":"10.21203/rs.3.rs-2592196/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"19807564-5f2f-4375-a52b-92f171be92c9","owner":[],"postedDate":"April 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":31068713,"name":"Biological sciences/Immunology/Innate immunity/Pattern recognition receptors/Toll-like receptors"},{"id":31068714,"name":"Biological sciences/Microbiology/Microbial communities/Microbiome"},{"id":31068715,"name":"Health sciences/Medical research/Translational research"},{"id":31068716,"name":"Health sciences/Medical research/Experimental models of disease"},{"id":31068717,"name":"Biological sciences/Immunology/Infectious diseases/Bacterial infection"}],"tags":[],"updatedAt":"2024-04-23T18:43:52+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-23 18:43:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-2592196","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2592196","identity":"rs-2592196","version":["v2"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}