Shigella mediated regulation of epithelial cell inflammasomes

志贺氏菌是人类重要的、高度传染性的病原体。2016年，有大约2.69亿起案件 另有21.2万人死于志贺氏菌。志贺氏菌感染与新生的炎症有关 中性粒细胞扩散到结肠和大量组织破坏。尽管东道主的反应令人印象深刻，志贺氏菌 在这种恶劣的环境中生存，主要是通过在结肠上皮细胞内复制和在其间扩散 (ECS)。志贺氏菌通过~30活性直接篡夺和重新编程宿主细胞过程而生存 III型效应器，它们通过高度保守的III型分泌物直接注入宿主细胞胞浆的蛋白质 系统(T3SS)。我们研究的总体目标是使用志贺氏菌作为模式病原体来破译其机制 使细胞内的病原体能够逃避宿主的先天性免疫反应，并建立一个复制的利基环境 肠内皮细胞的胞浆。我们对识别和破译效应器的角色有着长期的兴趣 志贺氏菌致病的具体步骤。志贺氏菌和其他肠道病原体面临的第一道防线 一旦试图在胃肠道内建立一个复制的生态位，就会导致肠道死亡 上睑下垂引起的ECS。上睑下垂是一种炎症形式的细胞死亡，如果不加以抑制，会导致迅速溶解。 和/或将感染的内皮细胞从肠上皮中排出，并加工和释放前... 炎性细胞因子。在这里，我们建议研究志贺氏菌III型分泌效应器是如何协同作用的 抑制下垂，从而使这种专业的胞浆内病原体在 肠上皮细胞的胞浆。这些研究的目的是显著扩大我们对 志贺氏菌和可能的其他肠道病原体是如何抑制炎症体的。在完成拟议的目标时， 所获得的知识可望应用于新型主体基材料的开发 预防和治疗肠道感染的干预措施，这是一项特别紧迫的需要，因为正在出现 抗生素耐药性的问题。

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 and 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.