Immune Complexes of SARS-CoV-2 RNA and Nucleocapsid Drive Inflammation

Immune complexes built from SARS-CoV-2 RNA, the viral nucleocapsid protein and anti-nucleocapsid IgG1 antibodies can drive the runaway inflammation seen in severe COVID-19, according to a laboratory study published in PLOS Pathogens. Researchers found that when these RNA-containing complexes are taken up by primary human monocytes, the cells produce inflammatory cytokines and chemokines in a response that depends on Fcγ receptors and is partially dependent on toll-like receptor 8.

The team, led by Johannes S. Gach and colleagues, traced how this phagocytic uptake translates into tissue damage. When monocytes were stimulated with the RNA-containing immune complexes, the inflammatory response they mounted caused endothelial dysfunction in vascularized micro-organs, laboratory models of human blood vessels. This links antibody-assisted clearance of viral material to a hallmark of severe disease: injury to the vascular lining.

The study also addressed where such complexes come from. Using nasopharyngeal samples from SARS-CoV-2-infected individuals, the researchers captured SARS-CoV-2 RNA and nucleocapsid protein with an anti-nucleocapsid monoclonal antibody without using lysing reagents. That result indicates the RNA and nucleocapsid complexes exist outside of virions and cells in the airways, making them available to form inflammatory immune complexes with circulating antibodies.

Consistent with a role for IgG-mediated inflammatory clearance in disease severity, the authors report that during an early wave of COVID-19, higher anti-nucleocapsid IgG:IgM ratios were associated with more severe clinical outcomes. They suggest this pattern fits a model in which inflammatory, IgG-driven phagocytic clearance of nucleic acid-containing immune complexes contributes to pathogenesis, while non-inflammatory, IgM-mediated clearance might mitigate it. As an observational association from one early pandemic wave, this finding supports but does not prove that mechanism.

The authors conclude that RNA-containing immune complexes may play a role in the pathogenesis of severe COVID-19. Because all pathogenic viruses encode nucleic acid-binding proteins similar to nucleocapsid, and these proteins often elicit antibody responses, they propose that inflammatory clearance of nucleic acid-containing immune complexes could also contribute to severity in other viral infections. As the work relies on in vitro monocyte assays, micro-organ models and patient sample analyses rather than direct clinical intervention studies, the findings define a plausible inflammatory mechanism and generate hypotheses for future research into severe viral disease rather than establishing treatment effects.

Subject of Research: How SARS-CoV-2 RNA-containing immune complexes drive inflammatory cytokine production and endothelial dysfunction in severe COVID-19.

Article Title: Phagocytosis of SARS-CoV-2 nucleocapsid- and RNA-containing immune complexes drives inflammatory cytokine production and endothelial dysfunction

Article References: Gach, J. S., Kim, D., Vu, K., Marshall, M., Cachay, C., Rangwala, A. A., Kerster, G., Tifrea, D., Pearlman, E., Zahn, M., van Gils, M., Hughes, C. C. W., & Forthal, D. N. (2026). Phagocytosis of SARS-CoV-2 nucleocapsid- and RNA-containing immune complexes drives inflammatory cytokine production and endothelial dysfunction. PLOS Pathogens, 22(10), e1014664. https://doi.org/10.1371/journal.ppat.1014664

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014664

Keywords: SARS-CoV-2, immune complexes, nucleocapsid protein, monocytes, Fcγ receptors, toll-like receptor 8, cytokines, endothelial dysfunction, COVID-19 severity, IgG:IgM ratio, PLOS Pathogens, Phagocytosis