Poster abstracts

Poster number 81 submitted by Mostafa Eltobgy

Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by mediating immunothrombosis

Mostafa Eltobgy (Neuroscience Graduate Program), Ashley Zani (Department of Microbial infection and immunity), Andrea Tedeschi (Department of Neuroscience), Shahid Nimjee (Department of Neurosurgery), Jacob Yount (Department of Microbial infection and immunity), Amal Amer (Department of Microbial infection and immunity)

Abstract:
SARS-CoV-2 infections are a worldwide health concern, and new treatment strategies are needed for decreasing virus-induced inflammatory tissue damage. Severe inflammatory response and coagulopathy are the hallmarks of severe Covid-19. Targeting inflammatory innate immunity pathways holds therapeutic promise, but effective molecular targets remain elusive.
Here, we show that the innate immunity proteins, 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 experienced less severe infections in terms of weight loss and lung damage than WT mice. Notably, these phenotypes were not recapitulated in mice lacking the CASP11 downstream effector gasdermin D (Gsdmd-/-), though viral titers were similar in all groups. Global transcriptomics of infected WT and Casp11-/- lungs identified decreased inflammation and neutrophil gene signatures. We confirmed that protein levels of inflammatory mediators IL-1β and CXCL1, and neutrophil infiltration, were decreased in Casp11-/- lungs. Additionally, Casp11-/- lungs accumulated less von Willebrand factor, a marker for endothelial injury/activation, but expressed more Kruppel-Like Factor 2, a transcription factor that maintains vascular integrity.
These findings establish CASP11 as an upstream regulator endothelial cell dysfunction and coagulopathy in SARS-CoV-2 infection largely independently of GSDMD. Overall, our results demonstrate that CASP11, promotes detrimental SARS-CoV-2-associated inflammation and coagulopathy, identifying CASP11 as a promising drug target for treatment and prevention of tissue damage in COVID-19.

Keywords: SRAS-CoV-2, Immunothrombosis, Caspase4