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

• Type of Material: Article
• Authors: Amy Girard, Emory University; Mostafa M Eltobgy, The Ohio State University College of Medicine; Ashely Zani, The Ohio State University College of Medicine; Adam D Kenney, The Ohio State University College of Medicine; Shady Estfanous, The Ohio State University College of Medicine; Eunsoo Kim, The Ohio State University; Asmaa Badr, The Ohio State University College of Medicine; Cierra Carafice, The Ohio State University College of Medicine; Kylene Daily, The Ohio State University College of Medicine; Owen Whitham, The Ohio State University College of Medicine; Maciej Pietrzak, The Ohio State University; Amy Webb, The Ohio State University; Jeffrey Kawahara, The Ohio State University College of Medicine; Adrian C Eddy, The Ohio State University College of Medicine; Parker Denz, The Ohio State University College of Medicine; Mijia Lu, The Ohio State University; KC Mahesh, The Ohio State University; Mark Ea Peeples, The Ohio State University; Jianrong Li, The Ohio State University; Jian Zhu, The Ohio State University; Jianwen Que, Columbia University; Richard Robinson, The Ohio State University College of Medicine; Oscar Rosas Mejia, The Ohio State University College of Medicine; Rachael E Rayner, The Ohio State University; Luanne Hall-Stoodley, The Ohio State University College of Medicine; Stephanie Seveau, The Ohio State University College of Medicine; Mikhail A Gavrilin, The Ohio State University; Xiaoli Zhang, The Ohio State University; Jeronay Thomas, Emory University; Jacob Kohlmeier, Emory University; Mehul Suthar, Emory University; Eugene Oltz, The Ohio State University College of Medicine; Andrea Tedeschi, The Ohio State University; Frank H Robledo-Avila, Nationwide Children’s Hospital; Santiago Partida-Sanchez, Nationwide Children’s Hospital; Emily A Hemann, The Ohio State University College of Medicine; Eman Abdelrazik, Nile University; Adriana Forero, The Ohio State University College of Medicine; Shahid M Nimjee, The Ohio State University; Prosper N Boyaka, The Ohio State University; Estelle Cormet-Boyaka, The Ohio State University; Jacob S Yount, The Ohio State University College of Medicine; Amal O Amer, The Ohio State University College of Medicine
• Language: English
• Date: 2022-05-24
• Publisher: PNAS
• Publication Version: Final Published Version
• Copyright Statement: © 2022 the Author(s). Published by PNAS.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.2202012119
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences of the United States of America
• Volume: 119
• Issue: 21
• Start Page: e2202012119
• End Page: e2202012119
• Keywords: Disease Progression; thrombosis; Thromboinflammation; Humans; Animals; Lung; SARS–CoV-2; Caspases, Initiator; COVID-19; Severity of Illness Index; Mice, Knockout; Mice; SARS-CoV-2; innate immunity
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

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 Casp112/2 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 (Gsdmd2/2). Notably, viral titers were similar regardless of CASP11 knockout. Global transcriptomics of SARS–CoV-2–infected WT, Casp112/2, and Gsdmd2/2 lungs identified restrained expression of inflammatory molecules and altered neutrophil gene signatures in Casp112/2 mice. We confirmed that protein levels of inflammatory mediators interleukin (IL)-1β, IL-6, and CXCL1, as well as neutrophil functions, were reduced in Casp112/2 lungs. Additionally, Casp112/2 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.