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 1

CASP11 deficiency protects against severe SARS-CoV-2 infection, limits early hyperinflammation, and enhances IFN-γ responses.

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CASP11 deficiency protects against severe SARS-CoV-2 infection, limits e...
(A) Body weight change in WT and Casp11–/– mice after i.n. infection with 5 × 105 TCID50 of MA10 SARS-CoV-2. WT mice exhibited more severe weight loss and slower recovery through day 14 compared with Casp11–/– mice (n = 26/group). Statistical analysis: 1-way ANOVA with Šídák’s multiple-comparison test. (B) PenH, as a surrogate of airway resistance, measured by whole-body plethysmography at multiple time points after infection, showing significantly lower resistance in Casp11–/– mice, indicative of improved lung function (n = 10 WT, n = 12 Casp11–/–). Statistical analysis: 2-way ANOVA with Šídák’s multiple-comparison test. (C) Principal component analysis (PCA) of variance-stabilized RNA-Seq data revealed distinct transcriptional profiles between WT and Casp11–/– lungs at day 4 after infection (5 × 105 TCID50 of MA10). PC1 accounted for 55% and PC2 for 17% of total variance. PERMANOVA analysis confirmed statistically significant separation between groups (R2 = 0.343, F = 3.135, P = 0.05, 999 permutations), indicating that genotype accounts for 34.3% of total transcriptional variance. Homogeneity of group dispersions was confirmed by betadisper analysis (F = 0.205, P = 0.554), validating the PERMANOVA result (n = 4/group). (D) GO enrichment analysis of genes with higher gene expression in Casp11–/– lungs compared with WT reveals enrichment in IFN signaling pathways and antiviral immune pathways (n = 4/group). (E) GO enrichment analysis of genes with lower gene expression in Casp11–/– lungs compared with WT highlights suppression of innate immune pathways, including myeloid cell chemotaxis and migration (n = 4/group). (F) Heatmap of differentially expressed cytokine and chemokine genes shows a shift in Casp11–/– lungs from pro-myeloid inflammation (e.g., Cxcl1, Il6, Ccl22) to lymphocyte-promoting responses (e.g., Ccl3, Ccl5, Ifng) (n = 4/group). ****P < 0.0001.