Caspase-11–mediated hyperinflammation impairs CD8+ T cell immunity and viral clearance in severe SARS-CoV-2 infection

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.

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Publication Details

Journal
JCI Insight
Published
2026-09-21
DOI
https://doi.org/10.1172/jci.insight.199896
Primary Topic
Inflammasome and immune disorders
Type
article
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article

Caspase-11–mediated hyperinflammation impairs CD8+ T cell immunity and viral clearance in severe SARS-CoV-2 infection

Jihad I. Omran, Maciej Pietrzak, Mostafa M. Eltobgy, Amir Yousif et al.
JCI Insight
Inflammasome and immune disorders
article

Caspase-11–mediated hyperinflammation impairs CD8+ T cell immunity and viral clearance in severe SARS-CoV-2 infection

Jihad I. Omran, Maciej Pietrzak, Mostafa M. Eltobgy, Amir Yousif, Hazem E. Ghoneim, Benjamin Matthew Segal, Estelle Cormet‐Boyaka, Adam D. Kenney, Kylene P. Daily, Sarah E. Faber, Andrew Mcnamara, Prosper N. Boyaka, Jeffrey R. Atkinson, Yara Y. Hassan, Purnima Dubey, Xiaoli Zhang, Gauruv Gupta, Heba M. Amer, Jesse M. Hall, Emily A. Hemann, Amal O. Amer, Mark E. Peeples, Asmaa Badr, Mohamed M. Shamseldin, Marisa R. Joldrichsen, Richard Perez, Shahid M. Nimjee, Owen D. Whitham, Amy Webb, Rabab El-Mergawy, Mahesh KC, Jacob S. Yount, Jianrong Li, Destiny Bissell, Shady Estfanous
article en

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.

JCI InsightVol. 11(18)
Nationwide Children's Hospital (US), University of South Florida (US), The Ohio State University Wexner Medical Center (US), Neuroscience Institute (IT), Infectious Diseases Institute (UG), The Ohio State University (US), Helwan University (EG)
Good health and well-being
Openalex Percentile: Top 18%
Inflammasome and immune disorders
DOIOpen Access PDFOpenAlex
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