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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 21; p. e2202012119
• Main Authors: Eltobgy, Mostafa M, 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, Kc, Mahesh, Peeples, Mark E, Li, Jianrong, Zhu, Jian, Que, Jianwen, Robinson, Richard, Rosas Mejia, Oscar, Rayner, Rachael E, Hall-Stoodley, Luanne, Seveau, Stephanie, Gavrilin, Mikhail A, Zhang, Xiaoli, Thomas, Jeronay, Kohlmeier, Jacob E, Suthar, Mehul S, Oltz, Eugene, Tedeschi, Andrea, Robledo-Avila, Frank H, Partida-Sanchez, Santiago, Hemann, Emily A, Abdelrazik, Eman, Forero, Adriana, Nimjee, Shahid M, Boyaka, Prosper N, Cormet-Boyaka, Estelle, Yount, Jacob S, Amer, Amal O
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24-05-2022
• Subjects: Animals; Biological Sciences; Blood vessels; Body weight loss; Caspase-11; Caspase-4; Caspases, Initiator - genetics; Caspases, Initiator - metabolism; Coronaviruses; COVID-19; COVID-19 - enzymology; COVID-19 - pathology; Damage accumulation; Disease Progression; Health services; Homology; Humans; Inflammation; Innate immunity; Interleukin 6; Krueppel-like factor; Leukocytes (neutrophilic); Lung - pathology; Lungs; Mice; Mice, Knockout; Neutrophils; Respiratory diseases; SARS-CoV-2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Severity of Illness Index; Therapeutic targets; Thromboinflammation - enzymology; Thromboinflammation - genetics; Transcriptomics; Viral diseases; Von Willebrand factor; Weight loss; innate immunity; SARS–CoV-2; thrombosis
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2202012119

Severe acute respiratory syndrome coronavirus 2 (SARS–CoV-2) is a worldwide health concern, and new treatment strategies are needed. 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 homolog, caspase-11 (CASP11), are up-regulated 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) mice and mice lacking the caspase downstream effector gasdermin-D (Gsdmd−/−). Notably, viral titers were similar regardless of CASP11 knockout. 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 interleukin (IL)-1β, IL-6, and CXCL1, as well as 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–induced inflammation and coagulopathy, largely independently of GSDMD, identifying CASP4/11 as a promising drug target for treatment and prevention of severe COVID-19.