Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by promoting inflammation and thrombosis

Eltobgy, Mostafa; Zani, Ashley; Kenney, Adam D.; Estfanous, Shady; Kim, Eunsoo; Badr, Asmaa; Carafice, Cierra; Daily, Kylene; Whitham, Owen; Pietrzak, Maciej; Webb, Amy; Kawahara, Jeffrey; Eddy, Adrian C.; Denz, Parker; Lu, Mijia; Mahesh, KC; Peeples, Mark E.; Li, Jianrong; Zhu, Jian; Que, Jianwen; Robinson, Richard; Mejia, Oscar Rosas; Rayner, Rachael E.; Hall-Stoodley, Luanne; Seveau, Stephanie; Gavrilin, Mikhail A.; Tedeschi, Andrea; Partida-Sanchez, Santiago; Roberto, Frank; Hemann, Emily A.; Abdelrazik, Eman; Forero, Adriana; Nimjee, Shahid M.; Boyaka, Prosper; Cormet-Boyaka, Estelle; Yount, Jacob S.; Amer, Amal O.

SARS-CoV-2 is a worldwide health concern, and new treatment strategies are needed 1. Targeting inflammatory innate immunity pathways holds therapeutic promise, but effective molecular targets remain elusive. Here, we show that human caspase-4 (CASP4), and its mouse homologue, caspase-11 (CASP11), are upregulated in SARS-CoV-2 infections, and that CASP4 expression correlates with severity of SARS-CoV-2 infection in humans. SARS-CoV-2-infected Casp11-/- mice were protected from severe weight loss and lung pathology, including blood vessel damage, compared to wild-type (WT) and gasdermin-D knock out (Gsdmd-/-) mice. GSDMD is a downstream effector of CASP11 and CASP1. Notably, viral titers were similar in the three genotypes. Global transcriptomics of SARS-CoV-2-infected WT, Casp11-/- and Gsdmd-/- lungs identified restrained expression of inflammatory molecules and altered neutrophil gene signatures in Casp11-/- mice. We confirmed that protein levels of inflammatory mediators IL-1β, IL6, and CXCL1, and neutrophil functions, were reduced in Casp11-/- lungs. Additionally, Casp11-/- lungs accumulated less von Willebrand factor, a marker for endothelial damage, but expressed more Kruppel-Like Factor 2, a transcription factor that maintains vascular integrity. Overall, our results demonstrate that CASP4/11, promotes detrimental SARS-CoV-2-associated inflammation and coagulopathy, largely independently of GSDMD, identifying CASP4/11 as a promising drug target for treatment and prevention of severe COVID-19.