Caspase-11–mediated hyperinflammation impairs CD8+ T cell immunity and viral clearance in severe SARS-CoV-2 infection
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
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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Research Article Immunology Infectious disease Inflammation

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

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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Figure 4

CASP11 deficiency in hematopoietic immune cells enhances survival, reduces inflammation, and promotes T cell response after SARS-CoV-2 infection.

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CASP11 deficiency in hematopoietic immune cells enhances survival, reduc...
(A) Kaplan-Meier survival analysis of WT chimeras (WT → WT) and Casp11–/– chimeras (Casp11–/– → WT) after i.n. infection with 1 × 105 TCID50 of MA10 SARS-CoV-2. Casp11–/– chimeras (Casp11–/– → WT) after i.n. infection with 1 × 105 TCID50 of MA10 SARS-CoV-2(n = 24 WT chimeras, n = 30 Casp11–/– chimeras). (B) PenH, a surrogate of airway resistance, measured by whole-body plethysmography at day 3 after infection (n = 18/group). (C and D) Cellularity scores (C) and representative H&E-stained lung sections (original magnification, ×2 and ×10) (D) at day 4 after infection (n = 4/group). (E) Flow cytometric quantification of neutrophils (LY6G+) in lung tissue at day 4 after infection (n = 4/group). (F–H) RT-qPCR analysis of inflammatory mediators in lung tissue at day 4 after infection Ifng (F) Cxcl1 (G) Il6 (H) in Casp11–/– chimeras compared with WT chimeras (n = 5 infected WT chimeras, n = 6 infected Casp11–/– chimeras, n = 3 noninfected WT chimeras, n = 3 noninfected Casp11–/– chimeras). (I) SARS-CoV-2 N gene RNA copy number (RCN) in lung homogenates at day 7 after infection, quantified by RT-qPCR (n = 5 infected WT chimeras, n = 6 infected Casp11–/– chimeras, n = 4 noninfected WT chimeras, n = 4 noninfected Casp11–/– chimeras). (J and K) Flow cytometric quantification with intravascular CD45 labeling of lung parenchymal CD8+ T cells (J) and activated effector CD8+ T cells (CD62LloCD44hiCD69hi) (K) at day 7 after infection (n = 4 infected WT chimeras, n = 6 infected Casp11–/– chimeras, n = 4 noninfected WT chimeras, n = 4 noninfected Casp11–/– chimeras). (L) Frequency of IFN-γ+ CD8+ T cells among lung parenchymal CD8+ T cells after ex vivo stimulation with SARS-CoV-2 SN peptide mixture at day 7 after infection. (n = 4 infected WT chimeras, n = 6 infected Casp11–/– chimeras, n = 4 noninfected WT chimeras, n = 4 noninfected Casp11–/– chimeras). Statistical significance determined by (A) log-rank (Mantel-Cox) test, (B) 2-way ANOVA with Šídák’s multiple-comparison test, (C and E) unpaired Student’s t test, and (F–H, J, K, and L) 1-way ANOVA with Tukey’s multiple-comparison test. Noninfected controls were age-matched, naive chimeric mice that underwent identical irradiation and BM reconstitution. Data shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.