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

Eltobgy, M.; Zani, A.; Kenney, A.; Estfanous, S.; Kim, E.; Badr, A.; Carafice, C.; Daily, K.; Whitham, O.; Pietrzak, M.; Webb, A.; Kawahara, J.; Eddy, A.; Denz, P.; Lu, M.; KC, M.; Peeples, M.; Li, J.; Zhu, J.; Que, J.; Robinson, R.; Rosas Mejia, O.; Rayner, R.; Hall-Stoodley, L.; Seveau, S.; Gavrilin, M. A.; Tedeschi, A.; Partida-Sanchez, S.; Roberto, F.; Hemann, E.; Abdelrazik, E.; Forero, A.; Nimjee, S.; Boyaka, P.; Cormet-Boyaka, E.; Yount, J.; Amer, A.

doi:10.1101/2021.09.24.461743

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bioRxiv · 10.1101/2021.09.24.461743

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

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Abstract

SARS-CoV-2 is a worldwide health concern, and new treatment strategies are needed 1. 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 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) 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-/- 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 IL-1{beta}, IL6, and CXCL1, and 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-associated inflammation and coagulopathy, largely independently of GSDMD, identifying CASP4/11 as a promising drug target for treatment and prevention of severe COVID-19.

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Eltobgy, M., Zani, A., Kenney, A., Estfanous, S., Kim, E., Badr, A., Carafice, C., Daily, K., Whitham, O., Pietrzak, M., Webb, A., Kawahara, J., Eddy, A., Denz, P., Lu, M., KC, M., Peeples, M., Li, J., Zhu, J., Que, J., Robinson, R., Rosas Mejia, O., Rayner, R., Hall-Stoodley, L., Seveau, S., Gavrilin, M. A., Tedeschi, A., Partida-Sanchez, S., Roberto, F., Hemann, E., Abdelrazik, E., Forero, A., Nimjee, S., Boyaka, P., Cormet-Boyaka, E., Yount, J., Amer, A.. 2021-09-25. Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by promoting inflammation and thrombosis. https://doi.org/10.1101/2021.09.24.461743

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