Abstract
Severe SARS-CoV-2 infection is characterized by lung hyperinflammation, impaired IFN responses, and defective T cell activation, yet the molecular drivers of these immune dysregulations remain incompletely understood. Caspase-11 (CASP11), a key effector of the noncanonical inflammasome, has been shown to mediate an innate hyperinflammatory response and cytokine release in a mild SARS-CoV-2 infection model. However, the role played by CASP11 in severe SARS-CoV-2 disease and how it affects adaptive immunity has not been identified. Here, we found that CASP11 exacerbates severe SARS-CoV-2 pathogenesis by amplifying early innate immune responses while concurrently impairing antiviral CD8+ T cell immunity. Using global KO mice, hematopoietic BM chimeras, and Cx3cr1-expressing mononuclear phagocyte system cell–specific CASP11 deletion models, we show that targeting CASP11 reduces lung inflammation, promotes early NK cell–mediated IFN-γ production, and enhances robust virus-specific effector CD8+ T cell responses. This was associated with enhanced viral clearance and improved survival, even under lethal infection conditions. Importantly, CASP11-KO mice also exhibited faster resolution of postviral inflammation. These findings position CASP11 as a promising immunomodulatory target for acute and delayed manifestations of severe SARS-CoV-2 infection.
Authors
Mostafa M. Eltobgy, Mohamed M. Shamseldin, Owen D. Whitham, Heba M. Amer, Jeffrey R. Atkinson, Asmaa Badr, Jesse M. Hall, Gauruv Gupta, Yara Y. Hassan, Rabab El-Mergawy, Richard Perez, Sarah E. Faber, Maciej Pietrzak, Amy Webb, Xiaoli Zhang, Adam D. Kenney, Destiny Bissell, Jihad I. Omran, Shady Estfanous, Kylene P. Daily, Amir Yousif, Marisa R. Joldrichsen, Andrew McNamara, Mahesh KC, Mark E. Peeples, Emily A. Hemann, Hazem E. Ghoneim, Shahid M. Nimjee, Estelle Cormet-Boyaka, Jianrong Li, Prosper N. Boyaka, Jacob S. Yount, Benjamin M. Segal, Purnima Dubey, Amal O. Amer
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