<i>Shigella</i> OspC3 Suppresses Murine Cytosolic LPS Sensing

Abstract

Caspase-11 and its human duplicates caspase-4 and caspase-5 detect cytosolic LPS and trigger gasdermin D-dependent pyroptosis to eliminate intra-cytoplasmic bacterial threats. Shigella spp. are cytosol-invasive pathogens that cause acute diarrhea and bacillary dysentery leading to severe mortality and morbidity worldwide. Shigella flexneri, a typical example of the genus, invades host cells, rapidly escapes the phagocytic vacuole into the cytosol, and deploys an array of type III-secreted effectors to evade host cell defenses and successfully establish a replicative niche within the cytosol. S. flexneri expresses a hexa-acylated LPS that is potentially detected by caspase-11. However, the role of caspase-11 in S. flexneri defense is still unclear. It has been reported that the T3SS effector OspC3 suppresses cytosolic LPS sensing by inhibiting caspase-4, but does not bind to caspase-11, suggesting that Ospc3 may not inhibit caspase-11 activity. Here, we found that S. flexneri triggers responses through caspase-1 canonical inflammasome, but evades caspase-11 sensing. Surprisingly, we found that S. flexneri also uses OspC3 to inhibit murine caspase-11 activity, indicating that OspC3 suppresses cytosolic LPS detection in a broad array of mammals. Importantly, we demonstrate that S. flexneri employs OspC3 to prevent caspase-11- gasdermin D mediated pyroptosis in neutrophils, enabling the bacteria to disseminate and evade clearance.