tetano
Editor, Senior Moderator
JCI Insight
. 2026 Sep 22;11(18):e199896.
doi: 10.1172/jci.insight.199896.
Mostafa M Eltobgy 1 , Mohamed M Shamseldin 1 2 , Owen D Whitham 1 , Heba M Amer 1 , Jeffrey R Atkinson 3 4 , Asmaa Badr 1 , Jesse M Hall 1 , Gauruv Gupta 1 , Yara Y Hassan 1 , Rabab El-Mergawy 1 , Richard Perez 1 , Sarah E Faber 1 , Maciej Pietrzak 5 , Amy Webb 5 , Xiaoli Zhang 6 , Adam D Kenney 1 , Destiny Bissell 1 , Jihad I Omran 1 , Shady Estfanous 2 , Kylene P Daily 1 , Amir Yousif 1 , Marisa R Joldrichsen 7 , Andrew McNamara 1 , Mahesh Kc 8 , Mark E Peeples 8 9 , Emily A Hemann 1 , Hazem E Ghoneim 1 , Shahid M Nimjee 10 , Estelle Cormet-Boyaka 7 , Jianrong Li 7 , Prosper N Boyaka 7 , Jacob S Yount 1 9 , Benjamin M Segal 3 4 , Purnima Dubey 1 , Amal O Amer 1 9
Affiliations Expand
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.
Keywords: Adaptive immunity; COVID-19; Immunology; Infectious disease; Inflammation; Innate immunity.
. 2026 Sep 22;11(18):e199896.
doi: 10.1172/jci.insight.199896.
Caspase-11-mediated hyperinflammation impairs CD8+ T cell immunity and viral clearance in severe SARS-CoV-2 infection
Mostafa M Eltobgy 1 , Mohamed M Shamseldin 1 2 , Owen D Whitham 1 , Heba M Amer 1 , Jeffrey R Atkinson 3 4 , Asmaa Badr 1 , Jesse M Hall 1 , Gauruv Gupta 1 , Yara Y Hassan 1 , Rabab El-Mergawy 1 , Richard Perez 1 , Sarah E Faber 1 , Maciej Pietrzak 5 , Amy Webb 5 , Xiaoli Zhang 6 , Adam D Kenney 1 , Destiny Bissell 1 , Jihad I Omran 1 , Shady Estfanous 2 , Kylene P Daily 1 , Amir Yousif 1 , Marisa R Joldrichsen 7 , Andrew McNamara 1 , Mahesh Kc 8 , Mark E Peeples 8 9 , Emily A Hemann 1 , Hazem E Ghoneim 1 , Shahid M Nimjee 10 , Estelle Cormet-Boyaka 7 , Jianrong Li 7 , Prosper N Boyaka 7 , Jacob S Yount 1 9 , Benjamin M Segal 3 4 , Purnima Dubey 1 , Amal O Amer 1 9
Affiliations Expand
- PMID: 42770296
- PMCID: PMC13596723
- DOI: 10.1172/jci.insight.199896
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.
Keywords: Adaptive immunity; COVID-19; Immunology; Infectious disease; Inflammation; Innate immunity.