tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Pablo A Alvarez[SUP] 1 2 [/SUP], Carolina Chavez[SUP] 1 3 [/SUP], Yennifer Delgado[SUP] 1 2 [/SUP], Prashant Kaushal[SUP] 1 [/SUP], David W Buchholz[SUP] 1 [/SUP], David Austin[SUP] 3 [/SUP], Qian Li[SUP] 4 5 [/SUP], Yanying Yu[SUP] 6 [/SUP], Anne K Zaiss[SUP] 3 [/SUP], Vaithilingaraja Arumugaswami[SUP] 3 7 [/SUP], Qiang Ding[SUP] 6 [/SUP], Jeffrey J Hsu[SUP] 4 5 8 [/SUP], Robert Damoiseaux[SUP] 3 5 9 [/SUP], Hector C Aguilar[SUP] 1 [/SUP], Mehdi Bouhaddou[SUP] 1 2 10 [/SUP], Alexander Hoffmann[SUP] 1 2 10 [/SUP], Melody M H Li[SUP] 1 2 7 [/SUP]
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[SUP] 1 [/SUP], Pablo A Alvarez[SUP] 1 2 [/SUP], Carolina Chavez[SUP] 1 3 [/SUP], Yennifer Delgado[SUP] 1 2 [/SUP], Prashant Kaushal[SUP] 1 [/SUP], David W Buchholz[SUP] 1 [/SUP], David Austin[SUP] 3 [/SUP], Qian Li[SUP] 4 5 [/SUP], Yanying Yu[SUP] 6 [/SUP], Anne K Zaiss[SUP] 3 [/SUP], Vaithilingaraja Arumugaswami[SUP] 3 7 [/SUP], Qiang Ding[SUP] 6 [/SUP], Jeffrey J Hsu[SUP] 4 5 8 [/SUP], Robert Damoiseaux[SUP] 3 5 9 [/SUP], Hector C Aguilar[SUP] 1 [/SUP], Mehdi Bouhaddou[SUP] 1 2 10 [/SUP], Alexander Hoffmann[SUP] 1 2 10 [/SUP], Melody M H Li[SUP] 1 2 7 [/SUP]
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.