Caspase11 modulates the adaptive immune response in SARS-CoV-2 infection through innate immune regulation 4503

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Abstract Description Caspase 11 is a critical component of the noncanonical inflammasome with multifaceted roles in the innate immune response, contributing to host defense against pathogens. We demonstrated that Casp11 deletion improved disease outcomes in SARS-CoV-2 infection by modulating the innate inflammatory response. However, its role in shaping adaptive immune responses after SARS-CoV-2 infection remains unclear. We found that Casp11-/- MA10 infected mice exhibited higher numbers of activated lung resident memory T cells at Day 7 post-infection compared to wild-type (WT) controls, independent of lung viral load. Ex vivo stimulation of lung-resident T cells with SARS-CoV-2 peptides and tetramer staining revealed that T cells from Casp11-/- mice retained their activation status, antigen specificity, and phenotype. This suggests that Casp11 deletion promotes the expansion and activation of lung resident T cells without impairing their functionality. Using Casp11-/- bone marrow chimera and Casp11-/- Cre-flox mouse models, we identified that the enhanced adaptive immune response was mediated by Casp11 in peripheral immune cells, particularly myeloid cells. These findings indicate that Casp11 deletion leads to a more robust lung-resident adaptive immune response by modulating the early innate immune response. This enhanced adaptive immunity contributed to more effective viral clearance, improved infection control, and reduced progression to severe disease in a P30 severe infection model. Funding Sources NIH 1P01AI175399-01A1 NIH 5R01HL168501-02 Topic Categories Viral Immunology (VIR)

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