Innate detection of replication triggers caspase-8-dependent apoptosis via TLR-driven TNF signaling and NLRC4-mediated sensing of the SPI-2 Type III secretion system.

comprises over 2500 serovars that are responsible for over 90 million annual infections and 100,000 deaths worldwide. Despite this diversity, our understanding of innate immune responses to is based on extensive study of a few serovars, primarily Typhimurium, including strains that cannot replicate within primary murine macrophages. Non-replicating trigger caspase-1 and -11-dependent pyroptosis. Whether the innate immune system distinguishes between replicating and non-replicating intracellular is poorly defined. Here we demonstrate that replicating induce a distinct pathway of TNF- and caspase-8-driven apoptosis via host TLR4 and Pathogenicity Island-2 activity. This pathway is independent of gasdermin D and involves the apoptotic pore protein Pannexin-1. Combined loss of Pannexin-1 and gasdermin D resulted in defective control of systemic , indicating that these pathways function together to promote anti- host defense. Altogether, our findings uncover a previously unappreciated pathway by which macrophages sense intracellular replicating bacteria.