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
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.