Shigella OspF blocks rapid p38-dependent priming of the NAIP-NLRC4 inflammasome

The NAIP-NLRC4 inflammasome senses pathogenic bacteria by recognizing the cytosolic presence of Bacterial proteins such as flagellin and type III secretion system (T3SS) subunits. In mice, the NAIP-NLRC4 inflammasome provides robust protection against Bacterial pathogens that infect intestinal epithelial cells, including the gastrointestinal pathogen Shigella flexneri . By contrast, humans are highly susceptible to Shigella , despite the ability of human NAIP-NLRC4 to robustly detect Shigella T3SS proteins. Why the NAIP-NLRC4 inflammasome protects mice but not humans against Shigella Infection remains unclear. We previously found that human THP-1 cells infected with Shigella lose responsiveness to NAIP-NLRC4 stimuli, while retaining sensitivity to Other inflammasome agonists. Using mT3Sf, a "minimal Shigella " system, to express individual secreted Shigella effector proteins, we found that the OspF effector specifically suppresses NAIP-NLRC4-dependent cell death during Infection. OspF was previously characterized as a phosphothreonine lyase that inactivates p38 and ERK MAP kinases. We found that p38 was critical for rapid priming of NAIP-NLRC4 activity, particularly in cells with low NAIP-NLRC4 expression. Overall, our results provide a mechanism by which Shigella evades inflammasome activation in humans, and describe a new mechanism for rapid priming of the NAIP-NLRC4 inflammasome.