Browsing by Author "Yao Zhenlan"

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    SARS-CoV-2 nucleocapsid induces hyperinflammation and vascular leakage through the Toll-like receptor signaling axis in macrophages
    (2026-8-7) Yao Zhenlan; Alvarez Pablo A.; Chavez Carolina; Delgado Yennifer; Kaushal Prashant; Buchholz David W.; Austin David; Li Qian; Yu Yanying; Zaiss Anne K.; Arumugaswami Vaithilingaraja; Ding Qiang; Hsu Jeffrey J.; Damoiseaux Robert; Aguilar Hector C.; Bouhaddou Mehdi; Hoffmann Alexander; Li Melody M. H.
    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.