Authors
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.
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.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 04 Nov 2025.
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