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.

志贺氏菌是人类的重要，高度感染性的病原体。在2016年，有约2.69亿个案件 志贺氏菌造成的212,000人死亡。志贺氏菌感染与由于招募而引起的炎症 嗜中性粒细胞到结肠和巨大的组织破坏。尽管有这种令人印象深刻的主人反应，Shigella 在这种严酷的环境中生存，主要是通过在结肠上皮细胞之间复制和扩散 （EC）。志贺氏菌通过直接篡改和重新编程的宿主细胞过程来生存 III型效应子，通过高度保守的III型分泌直接注入宿主细胞胞质的蛋白质 系统（T3SS）。我们的研究的总体目标是使用志贺氏菌作为模型病原体来破译机制 这使细胞内病原体能够逃避宿主的先天免疫反应，并建立一个复制的生态位 肠道EC的细胞质。我们对识别和破译效应子的角色一直很感兴趣 在志贺氏菌发病机理的特定步骤中。 Shigella和其他肠道病原体面对的第一道防线 试图在胃肠道内建立复制生态位，是肠道死亡的诱导 EC通过凋亡。凋亡是一种细胞死亡的炎症形式，如果不抑制，会导致快速裂解 和/或从肠上皮中驱逐感染EC以及促进和释放 炎症细胞因子。在这里，我们建议调查志贺氏奇型III型分泌效应子如何合作 抑制凋亡，从而使这种专业的胞质内病原体能够在 肠上皮细胞的细胞质。这些研究旨在显着扩大我们对 志贺氏菌以及可能的其他肠道病原体如何抑制炎症。拟议的目标完成时， 预计所获得的知识可以应用于开发基于新型宿主的新知识 预防和治疗肠道感染的干预措施，出现了特别紧迫的需求 抗生素抗性的问题。