SARS-CoV-2 nucleocapsid induces hyperinflammation and vascular leakage through the Toll-like receptor signaling axis in macrophages

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Abstract
A substantial proportion of hospitalized COVID-19 patients require ICU admission, often associated with an imbalance between antiviral responses and inflammatory signaling leading to uncontrolled cytokine secretion. The SARS-CoV-2 nucleocapsid (N) protein is a known immune antagonist, but its role in macrophage-driven cytokine storms is unclear. We demonstrate that N functions in a stimulus-specific manner, specifically amplifying extracellular and dampening intracellular RNA sensing. Moreover, we show that this is a conserved feature of pathogenic betacoronaviruses through distinct mechanisms. Our interaction networks with SARS-CoV-2 variant N proteins suggest that the Delta variant N drives inflammation through interactions with several proteins, most notably, cGAS. Profiling of secreted cytokines revealed that N disrupts the secretome in a variant-specific manner. Most notably, we found that supernatants from the Delta variant N–expressing macrophages dramatically disrupt heart endothelial barriers, implicating N in COVID-19–associated cardiac complications. Our findings highlight N-mediated immune imbalance as a driver of severe COVID-19 and identify N as a promising therapeutic target to mitigate hyperinflammation.
Funding Information
  • National Institute of Allergy and Infectious Diseases (F31AI179235)
  • National Institute of Allergy and Infectious Diseases (R01AI173214)
  • National Institute of Allergy and Infectious Diseases (R01AI185026)
  • National Institute of Allergy and Infectious Diseases (5P30 AI028697)
  • National Institute of Allergy and Infectious Diseases (R01AI109022)
  • National Institute of Allergy and Infectious Diseases (R01AI158704)
  • W. M. Keck Foundation (UCLA DGSOM Junior Faculty Award)
  • American Heart Association (Mechanisms Underlying Cardiovascular Consequences Associated with COVID-19 and Long COVID Award)
  • Ruth L. Kirschstein National Research Service (Award AI007323 (DWB))
  • UCLA Microbiology, Immunology and Molecular Genetics (Sydney Finegold Post-Doctoral Fellow Award)
  • UCLA DGSOM - Broad Stem Cell Research Center (COVID-19 Research Award)
  • Jonsson Comprehensive Cancer Center-Broad Stem Cell Research Center (Ablon Scholars Award)

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