<i>Shigella</i> 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 <i><i>Shigella</i> flexneri</i>. By contrast, humans are highly susceptible to <i><i>Shigella</i></i>, despite the ability of human NAIP-NLRC4 to robustly detect <i><i>Shigella</i></i> T3SS proteins. Why the NAIP-NLRC4 inflammasome protects mice but not humans against <i><i>Shigella</i></i> infection remains unclear. We previously found that human THP-1 cells infected with <i><i>Shigella</i></i> lose responsiveness to NAIP-NLRC4 stimuli, while retaining sensitivity to other inflammasome agonists. Using mT3Sf, a "minimal <i><i>Shigella</i></i>" system, to express individual secreted <i><i>Shigella</i></i> 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 <i><i>Shigella</i></i> evades inflammasome activation in humans, and describe a mechanism for rapid priming of the NAIP-NLRC4 inflammasome.