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Sci Adv
. 2026 Aug 7;12(32):eaea2780.
doi: 10.1126/sciadv.aea2780. Epub 2026 Aug 5.
SARS-CoV-2 nucleocapsid induces hyperinflammation and vascular leakage through the Toll-like receptor signaling axis in macrophages
Zhenlan Yao 1 , Pablo A Alvarez 1 2 , Carolina Chavez 1 3 , Yennifer Delgado 1 2 , Prashant Kaushal 1 , David W Buchholz 1 , David Austin 3 , Qian Li 4 5 , Yanying Yu 6 , Anne K Zaiss 3 , Vaithilingaraja Arumugaswami 3 7 , Qiang Ding 6 , Jeffrey J Hsu 4 5 8 , Robert Damoiseaux 3 5 9 , Hector C Aguilar 1 , Mehdi Bouhaddou 1 2 10 , Alexander Hoffmann 1 2 10 , Melody M H Li 1 2 7
Affiliations
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.
. 2026 Aug 7;12(32):eaea2780.
doi: 10.1126/sciadv.aea2780. Epub 2026 Aug 5.
SARS-CoV-2 nucleocapsid induces hyperinflammation and vascular leakage through the Toll-like receptor signaling axis in macrophages
Zhenlan Yao 1 , Pablo A Alvarez 1 2 , Carolina Chavez 1 3 , Yennifer Delgado 1 2 , Prashant Kaushal 1 , David W Buchholz 1 , David Austin 3 , Qian Li 4 5 , Yanying Yu 6 , Anne K Zaiss 3 , Vaithilingaraja Arumugaswami 3 7 , Qiang Ding 6 , Jeffrey J Hsu 4 5 8 , Robert Damoiseaux 3 5 9 , Hector C Aguilar 1 , Mehdi Bouhaddou 1 2 10 , Alexander Hoffmann 1 2 10 , Melody M H Li 1 2 7
Affiliations
- PMID: 42555728
- DOI: 10.1126/sciadv.aea2780
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.