Shigella mediated regulation of epithelial cell inflammasomes

志贺氏菌介导的上皮细胞炎症小体的调节

• 批准号: 10608342
• 负责人: CAMMIE LESSER
• 金额: $ 76.16万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-14 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608342
• 关键词: Actins; Acute; Antibiotic Resistance; Bacteria; Binding; Binding Proteins; CASP1 gene; CASP4 gene; CASP5 gene; Caspase; Cell Death; Cell membrane; Cell physiology; Cells; Cessation of life; Collaborations; Colon; Complex; Cytolysis; Cytosol; Data; Development; Diarrhea; Environment; Epithelial Cells; Epithelium; Face; Future; GBP1 gene; Gastrointestinal tract structure; Goals; Growth; Host Defense; Human; IL18 gene; Immune response; Infection; Infection prevention; Inflammasome; Inflammation; Inflammatory; Innate Immune Response; Interferons; Interleukin-1 beta; Interruption; Intervention; Invaded; Ions; Knowledge; Learning; Lipid A; Lipopolysaccharides; Mediating; Modeling; Modification; Mus; N-terminal; Neutrophil Infiltration; Oral; Orthologous Gene; OspC protein; Pathogenesis; Peptide Hydrolases; Persons; Prevention; Process; Proteins; Regulation; Research; Role; Shigella; Shigella Infections; Specificity; Swelling; Testing; Tissues; Type III Secretion System Pathway; Ubiquitin; Variant; Work; cell motility; cytokine; design; enteric infection; enteric pathogen; gain of function; guanylate; gut inflammation; human pathogen; improved; innovation; interest; intestinal epithelium; neutrophil; novel; pathogen; pathogenic bacteria; recruit; sensor

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.

志贺氏菌属是人类重要的高传染性病原体。2016年，约有2.69亿例 21.2万人死于志贺氏菌志贺氏菌感染与炎症有关， 嗜中性粒细胞扩散到结肠并造成大量组织破坏尽管宿主的反应令人印象深刻， 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结肠上皮细胞之间传播 （EC）。志贺氏菌通过~30的活性直接篡夺和重编程宿主细胞过程而存活 III型效应物，它们通过高度保守的III型分泌直接注入宿主细胞胞质溶胶的蛋白质 系统（T3 SS）。我们的研究的总体目标是使用志贺氏菌作为模式病原体来破译机制 使细胞内病原体能够逃避宿主的先天免疫反应，并建立一个复制生态位， 肠内皮细胞的胞质溶胶。我们有一个长期的兴趣在识别和破译的作用效应 志贺氏菌致病的特定步骤。志贺氏菌和其他肠道病原体面临的第一道防线 当试图在胃肠道内建立一个复制生态位时， 通过焦亡引起的内皮细胞损伤细胞凋亡是一种炎症性细胞死亡，如果不加以抑制， 和/或受感染的EC从肠上皮中排出，以及前- 炎性细胞因子在这里，我们建议调查如何志贺氏菌III型分泌的效应合作， 抑制焦亡，从而使这种专业的胞质内病原体建立一个复制生态位内 肠上皮细胞的细胞质。这些研究旨在显著扩大我们对 志贺氏菌和其他可能的肠道病原体如何抑制炎性小体。在完成拟议目标时， 预计所获得的知识可以应用于开发新的基于主机的 预防和治疗肠道感染的干预措施，这是一个特别迫切的需要， 抗生素耐药性的问题。