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Given the persistence of SARS-Cov-2 RNA and nucleocapsid protein (N) and the presence of anti-N antibody during the course of severe infection, we investigated the role of RNA-containing immune complexes (ICs) in driving inflammation. We found that ICs consisting of SARS-CoV-2 RNA, N, and anti-N IgG1 are internalized by primary human monocytes and stimulate inflammatory cytokines and chemokines in a manner dependent on Fc\u03b3 receptors and partially dependent on toll-like receptor-8. In addition, the inflammatory response induced in monocytes by RNA-containing ICs caused endothelial dysfunction in vascularized micro-organs. Using nasopharyngeal samples from SARS-CoV-2-infected individuals, SARS-CoV-2 RNA and N were captured by anti-N monoclonal antibody in the absence of lysing reagents, indicating that SARS-CoV-2 RNA and N complexes are present outside of virions and cells. Finally, we found that during an early wave of COVID-19, higher anti-N IgG:IgM ratios were associated with more severe clinical outcomes, consistent with a role for inflammatory, IgG-mediated phagocytic clearance of nucleic acid-containing ICs in SARS-CoV-2 pathogenesis, perhaps mitigated by non-inflammatory, IgM-mediated clearance. We conclude that RNA-containing ICs may play a role in the pathogenesis of severe COVID-19. Since all pathogenic viruses encode nucleic acid-binding proteins, such as N, and these proteins often elicit an antibody response, inflammatory clearance of nucleic acid-containing ICs may also contribute to disease severity in other viral infections.<\/jats:p>","DOI":"10.64898\/2026.04.09.717495","type":"posted-content","created":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T15:17:36Z","timestamp":1776007056000},"source":"Crossref","is-referenced-by-count":0,"title":["Phagocytosis of SARS-CoV-2 Nucleocapsid- and RNA-Containing Immune Complexes Drives Inflammatory Cytokine Production and Endothelial Dysfunction"],"prefix":"10.64898","author":[{"given":"Johannes S.","family":"Gach","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, University of California, Irvine School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology & Biochemistry, University of California, Irvine, School of Biological Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khoa","family":"Vu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, University of California, Irvine School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Marshall","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of California, Irvine School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Cachay","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, University of California, Irvine School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aminah A.","family":"Rangwala","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases, University of California, Irvine School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gius","family":"Kerster","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology & Infection Prevention, Amsterdam UMC, University of Amsterdam and Amsterdam Institute for Immunology and Infectious Diseases"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delia","family":"Tifrea","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California, Irvine School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Pearlman","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of California, Irvine School of Medicine"},{"name":"Department of Physiology and Biophysics, University of California, Irvine School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Zahn","sequence":"additional","affiliation":[{"name":"Pediatric Infectious Disease Division, Children\u2019s Hospital of Orange County"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3422-8161","authenticated-orcid":false,"given":"Marit","family":"van Gils","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology & Infection Prevention, Amsterdam UMC, University of Amsterdam and Amsterdam Institute for Immunology and Infectious Diseases"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C. 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