Shigella species are important highly infectious pathogens of humans. In 2016, there were ~269 million cases and 212,000 deaths due to Shigella. Infection with Shigella is associated with inflammation due to the recruitment of neutrophils to the colon and massive tissue destruction. Despite this impressive host response, Shigella survive in this harsh environment, primarily by replicating within and spreading between colonic epithelial cells (ECs). Shigella survive by directly usurping and reprogramming host cell processes through the activity of ~30 type III effectors, proteins that they directly inject into the host cell cytosol via a highly conserved type III secretion system (T3SS). Our research's overall goal is to use Shigella as a model pathogen to decipher the mechanisms that enable intracellular pathogens to evade host innate immune responses and establish a replicative niche with the cytosol of intestinal ECs. We have a long-standing interest in identifying and deciphering roles for effectors in specific steps in Shigella pathogenesis. The first line of defense that Shigella and other enteric pathogens face upon trying to establish a replicative niche within the gastrointestinal tract is the induction of the death of intestinal ECs via pyroptosis. Pyroptosis is an inflammatory form of cell death that, if not inhibited, results in the rapid lysis and/or expulsion of infected ECs from the intestinal epithelium, as well as the processing and release of pro- inflammatory cytokines. Here, we propose to investigate how Shigella type III secreted effectors cooperate to inhibit pyroptosis, thus enabling this professional intracytoplasmic pathogen to establish a replicative niche within the cytosol of intestinal epithelial cells. These studies are designed to significantly expand our understanding of how Shigella, and likely other enteric pathogens, inhibit inflammasomes. At the completion of the proposed aims, it is expected that the knowledge gained can be applied towards the development of novel host-based interventions for the prevention and treatment of enteric infections, a particularly pressing need given emerging issues with antibiotic resistance.