Phagocytosis of SARS-CoV-2 nucleocapsid- and RNA-containing immune complexes drives inflammatory cytokine production and endothelial dysfunction
7 affiliations
- 1Department of Medicine, Division of Infectious Diseases, University of California, Irvine School of Medicine, Irvine, California, United States of America
- 2Department of Molecular Biology & Biochemistry, University of California, Irvine, School of Biological Sciences, Irvine, California, United States of America
- 3Department of Ophthalmology and Visual Sciences, University of California, Irvine School of Medicine, Irvine, California, United States of America
- 4Department of Medical Microbiology & Infection Prevention, Amsterdam UMC, University of Amsterdam and Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands
- 5Department of Pathology, University of California, Irvine School of Medicine, Irvine, California, United States of America
- 6Department of Physiology and Biophysics, University of California, Irvine School of Medicine, Irvine, California, United States of America
- 7Pediatric Infectious Disease Division, Children’s Hospital of Orange County, Orange, California, United States of America
Abstract
The aberrant inflammation that characterizes severe COVID-19 is incompletely understood. 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 Fcγ 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. Author summary: Infection with SARS-CoV-2 can result in both severe acute disease and in chronic debilitating symptoms. We explored a mechanism by which the virus, even when no longer actively replicating, could provoke the type of inflammatory response associated with severe disease or long COVID. We found that immune complexes, consisting of SARS-CoV-2 RNA, the nucleocapsid protein that binds to the RNA, and antibodies that bind the nucleocapsid, stimulated human monocytes to produce an inflammatory response. This inflammatory response was due to the immune complexes triggering receptors on the surface and in the interior of the monocytes and required the presence of the RNA. The monocytes exposed to the immune complexes caused vascular leakage, a characteristic of severe COVID. We also found an association between the type of antibody response that triggered the inflammation in monocytes and COVID severity in a group of patients infected during an early wave of the pandemic. Our findings reveal a novel way in which SARS-CoV-2, and potentially other viruses, could initiate or sustain harmful inflammation.
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BibTeX
@article{gach2026phagocytosis,
title = {{Phagocytosis of SARS-CoV-2 nucleocapsid- and RNA-containing immune complexes drives inflammatory cytokine production and endothelial dysfunction}},
author = {Johannes S. Gach and Daniel Kim and Khoa Vu and Michaela Marshall and Christopher Cachay and Aminah A. Rangwala and Gius Kerster and Delia Tifrea and Eric Pearlman and Matthew Zahn and Marit van Gils and Christopher C. W. Hughes and Donald N. Forthal},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014664},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014664},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Phagocytosis of SARS-CoV-2 nucleocapsid- and RNA-containing immune complexes drives inflammatory cytokine production and endothelial dysfunction
AU - Johannes S. Gach
AU - Daniel Kim
AU - Khoa Vu
AU - Michaela Marshall
AU - Christopher Cachay
AU - Aminah A. Rangwala
AU - Gius Kerster
AU - Delia Tifrea
AU - Eric Pearlman
AU - Matthew Zahn
AU - Marit van Gils
AU - Christopher C. W. Hughes
AU - Donald N. Forthal
PY - 2026
DA - 2026/10/29
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014664
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014664
AB - The aberrant inflammation that characterizes severe COVID-19 is incompletely understood. 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 Fcγ 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. Author summary: Infection with SARS-CoV-2 can result in both severe acute disease and in chronic debilitating symptoms. We explored a mechanism by which the virus, even when no longer actively replicating, could provoke the type of inflammatory response associated with severe disease or long COVID. We found that immune complexes, consisting of SARS-CoV-2 RNA, the nucleocapsid protein that binds to the RNA, and antibodies that bind the nucleocapsid, stimulated human monocytes to produce an inflammatory response. This inflammatory response was due to the immune complexes triggering receptors on the surface and in the interior of the monocytes and required the presence of the RNA. The monocytes exposed to the immune complexes caused vascular leakage, a characteristic of severe COVID. We also found an association between the type of antibody response that triggered the inflammation in monocytes and COVID severity in a group of patients infected during an early wave of the pandemic. Our findings reveal a novel way in which SARS-CoV-2, and potentially other viruses, could initiate or sustain harmful inflammation.
SN - 1553-7374
ER -