Caspase-1 in Cx3cr1-expressing cells drives an IL-18-dependent T cell response that promotes parasite control during acute Toxoplasma gondii infection 2339

Abstract Description Inflammasome activation is a robust innate immune mechanism that promotes inflammatory responses through the release of cytokines, including IL-1a, IL-1b, and IL-18. Infectious agents can cause inflammasomes to assemble and activate caspase-1. Caspase-1 cleaves targets that lead to pore formation and cytokine release. Toxoplasma gondii promotes inflammasome formation, but the cell types utilizing caspase-1 and its immunological outcomes during acute in vivo infection have not been explored. Here, we examine caspase-1 responses during acute T. gondii infection globally and in Cx3cr1-positive populations. We provide in vivo evidence that caspase-1 expression is critical for, IL-18 release, optimal interferon-γ (IFN-g) production, monocyte and neutrophil recruitment, and parasite control. We find that caspase-1 in Cx3cr1-positive cells drives IL-18 release, potentiating CD4+ T cell IFN-γ production and parasite control. Cx3cr1-Casp1 knockouts exhibited a selective T cell defect, mirroring Il18 knockouts. Furthermore, treatment of Cx3cr1-Casp1 knockout mice with recombinant IL-18 restored IFN-γ responses and parasite control. Additionally, we show that neutrophil recruitment is dependent on IL-1 receptor accessory protein (IL-1RAP) signaling but is dispensable for parasite control. Overall, these experiments highlight the role of caspase-1 in multiple cell populations contributing to specific pathways that collectively contribute to caspase-1 dependent immunity to T. gondii. Funding Sources Supported by NIH grants (R01NS112516; R21NS128551; T32AI007496; 5T32GM136615; 5T32NS1156573; S10RR031633-01) and a Pinn Scholars Award from the University of Virginia Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)