Department of Microbiology and Immunology, Center for Microbial Pathogenesis and Host Responses, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Ambika Verma
Department of Microbiology and Immunology, Center for Microbial Pathogenesis and Host Responses, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Mohib Hafeez
Department of Microbiology and Immunology, Center for Microbial Pathogenesis and Host Responses, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; Department of Biology, University of Arkansas at Little Rock, Little Rock, AR 72204, USA
Brandon Hogland
Department of Microbiology and Immunology, Center for Microbial Pathogenesis and Host Responses, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Youssef Aachoui
Department of Microbiology and Immunology, Center for Microbial Pathogenesis and Host Responses, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; Corresponding author
Summary: Shigella 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 combating S. flexneri is unclear. The Shigella T3SS effector OspC3 reportedly suppresses cytosolic LPS sensing by inhibiting caspase-4 but not caspase-11 activity. Surprisingly, we found that S. flexneri also uses OspC3 to inhibit murine caspase-11 activity. Mechanistically, we found that OspC3 binds only to primed caspase-11. Importantly, we demonstrate that S. flexneri employs OspC3 to prevent caspase-11-mediated pyroptosis in neutrophils, enabling bacteria to disseminate and evade clearance following intraperitoneal challenge. In contrast, S. flexneri lacking 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.
