Authors
Zhenlan Yao, Pablo A Alvarez, Carolina Chavez, Yennifer Delgado, Prashant Kaushal, David W Buchholz, David Austin, Qian Li, Yanying Yu, Anne K Zaiss, Vaithilingaraja Arumugaswami, Qiang Ding, Jeffrey J Hsu, Robert Damoiseaux, Hector C Aguilar, Mehdi Bouhaddou, Alexander Hoffmann, Melody M H Li
Published in
Science advances. Volume 12. Issue 32. Pages eaea2780. Aug 07, 2026. Epub Aug 05, 2026.
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.
PMID:
42555728
Bibliographic data and abstract were imported from PubMed on 06 Aug 2026.
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