Caspase-11 Mediated Hyperinflammation Impairs CD8⁺ T Cell Immunity and Viral Clearance in Severe SARS-CoV-2 Infection

ELTOBGY, M.; Shamseldin, M.; Whitham, O.; Amer, H.; Atkinson, J.; Badr, A.; Hall, J.; Omran, J.; Gupta, G.; Hassan, Y.; Abdelaleem, R.; Perez, R.; Faber, S.; Pietrzak, M.; Webb, A.; Zhang, X.; Kenney, A.; Bissel, D.; Estfanous, S.; Daily, K.; Mcnamara, A.; KC, M.; Peeples, M.; Hemann, E.; Nimjee, S.; Cormet-Boyaka, E.; Li, J.; Boyaka, P.; Yount, J.; Segal, B.; Dubey, P.; Amer, A.

doi:10.1101/2025.11.01.684729

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bioRxiv · 10.1101/2025.11.01.684729

Caspase-11 Mediated Hyperinflammation Impairs CD8⁺ T Cell Immunity and Viral Clearance in Severe SARS-CoV-2 Infection

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Abstract

Severe SARS-CoV-2 infection is characterized by lung hyperinflammation, impaired interferon responses, and defective T-cell activation, yet the molecular drivers of these immune dysregulations remain incompletely understood. Caspase-11 (CASP11), a key mediator of the non-canonical inflammasome, has been shown to mediate an innate hyperinflammatory response and cytokine release in a non-severe, non-lethal SARS-CoV-2 infection model. However, the role played by CASP11 in severe SARS-CoV-2 disease and how it impacts adaptive immunity is not identified. Here, we newly discover that CASP11 exacerbates severe SARS-CoV-2 pathogenesis by amplifying early innate immune responses while concurrently impairing antiviral CD8 T-cell immunity. Using global knockouts, reciprocal bone marrow chimeras, and phagocyte-monocyte system (PMS) cell-specific CASP11 deletion models, we show that CASP11 deletion in monocyte-derived cells reduces lung inflammation, enhances type I and II interferon signaling, and promotes robust virus-specific effector CD8 T-cell response. This was associated with enhanced viral clearance and improved survival, even under lethal infection conditions. Importantly, CASP11 KO mice also exhibited faster resolution of post-viral inflammation, suggesting a role in long-term immune remodeling. These findings position CASP11 as a promising immunomodulatory target for acute and delayed manifestations of severe SARS-CoV-2.

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ELTOBGY, M., Shamseldin, M., Whitham, O., Amer, H., Atkinson, J., Badr, A., Hall, J., Omran, J., Gupta, G., Hassan, Y., Abdelaleem, R., Perez, R., Faber, S., Pietrzak, M., Webb, A., Zhang, X., Kenney, A., Bissel, D., Estfanous, S., Daily, K., Mcnamara, A., KC, M., Peeples, M., Hemann, E., Nimjee, S., Cormet-Boyaka, E., Li, J., Boyaka, P., Yount, J., Segal, B., Dubey, P., Amer, A.. 2025-11-03. Caspase-11 Mediated Hyperinflammation Impairs CD8⁺ T Cell Immunity and Viral Clearance in Severe SARS-CoV-2 Infection. https://doi.org/10.1101/2025.11.01.684729

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