| First Author | Eltobgy MM | Year | 2022 |
| Journal | Proc Natl Acad Sci U S A | Volume | 119 |
| Issue | 21 | Pages | e2202012119 |
| PubMed ID | 35588457 | Mgi Jnum | J:331823 |
| Mgi Id | MGI:7285890 | Doi | 10.1073/pnas.2202012119 |
| Citation | Eltobgy MM, et al. (2022) Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by promoting inflammation and immunothrombosis. Proc Natl Acad Sci U S A 119(21):e2202012119 |
| abstractText | 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)-1beta, 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. |
