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

• DOI: 10.1101/2021.09.24.461743
• Publication Date: 2021-09-25T23:40:10Z
• Authors: Mostafa Eltobgy; Ashley Zani; Adam D. Kenney; Shady Estfanous; Eunsoo Kim; Asmaa Badr; Cierra Carafice; Kylene Daily; Owen Whitham; Maciej Pietrzak; Amy Webb; Jeffrey Kawahara; Adrian C. Eddy; Parker Denz; Mijia Lu; KC Mahesh; Mark E. Peeples; Jianrong Li; Jian Zhu; Jianwen Que; Richard Robinson; Oscar Rosas Mejia; Rachael E. Rayner; Luanne Hall-Stoodley; Stephanie Seveau; Mikhail A. Gavrilin; Andrea Tedeschi; Santiago Partida-...; Frank Roberto; Emily A. Hemann; Eman Abdelrazik; Adriana Forero; Shahid M. Nimjee; Prosper Boyaka; Estelle Cormet-Bo...; Jacob S. Yount; Amal O. Amer
• Keywords: 0301 basic medicine; 03 medical and health sciences; 3. Good health

AbstractSARS-CoV-2 is a worldwide health concern, and new treatment strategies are needed1. 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 thatCASP4expression correlates with severity of SARS-CoV-2 infection in humans. SARS-CoV-2-infectedCasp11-/-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-/-andGsdmd-/-lungs identified restrained expression of inflammatory molecules and altered neutrophil gene signatures inCasp11-/-mice. We confirmed that protein levels of inflammatory mediators IL-1β, IL6, and CXCL1, and neutrophil functions, were reduced inCasp11-/-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.