摘要：SummaryShigella flexneri, a cytosol-invasive gram-negative pathogen, deploys an array of type III-secreted effector proteins to evade host cell defenses. Caspase-11 and its human ortholog caspase-4 detect cytosolic lipopolysaccharide (LPS) and trigger gasdermin D-mediated pyroptosis to eliminate intra-cytoplasmic bacterial threats.However, the role of caspase-11 in combatingS. flexneriis unclear. TheShigellaT3SS effector OspC3 reportedly suppresses cytosolic LPS sensing by inhibiting caspase-4 but not caspase-11 activity. Surprisingly, we found thatS. flexnerialso uses OspC3 to inhibit murine caspase-11 activity. Mechanistically, we found that OspC3 binds only to primed caspase-11. Importantly, we demonstrate thatS. flexneriemploys OspC3 to prevent caspase-11-mediated pyroptosis in neutrophils, enabling bacteria to disseminate and evade clearance following intraperitoneal challenge. In contrast,S. flexnerilacking OspC3 is attenuated in a caspase-11- and gasdermin D-dependent fashion. Overall, our study reveals that OspC3 suppresses cytosolic LPS detection in a broad array of mammals.Graphical abstractDisplay OmittedHighlights•S. flexneriT3SS-secreted OspC3 suppresses cytosolic LPS sensing by caspase-11•OspC3 binds to caspase-11 in a priming-dependent manner•S. flexneriemploys OspC3 to prevent caspase-11-mediated pyroptosis in neutrophils•Neutrophil caspase-11 is essential in defense againstS. flexneri ΔOspC3 in vivoImmunology; Microbiology
