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.

志贺氏菌是人类重要的、高度传染性的病原体。 2016年，约有2.69亿例病例 志贺氏菌导致 212,000 人死亡。志贺氏菌感染与由于募集引起的炎症有关 中性粒细胞进入结肠并造成大量组织破坏。尽管宿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传播 （EC）。志贺氏菌通过〜30的活性直接篡夺和重新编程宿主细胞过程而生存 III 型效应子，通过高度保守的 III 型分泌直接注射到宿主细胞胞质中的蛋白质 系统（T3SS）。我们研究的总体目标是使用志贺氏菌作为模型病原体来破译其机制 使细胞内病原体能够逃避宿主先天免疫反应并建立复制生态位 肠 EC 的细胞质。我们长期以来对识别和解读效应器的角色感兴趣 志贺氏菌发病机制的具体步骤。志贺氏菌和其他肠道病原体面临的第一道防线 当试图在胃肠道内建立复制生态位时，会诱导肠道死亡 EC通过细胞焦亡。细胞焦亡是细胞死亡的一种炎症形式，如果不加以抑制，会导致细胞快速裂解 和/或将受感染的 EC 从肠上皮中排出，以及前体的加工和释放 炎症细胞因子。在这里，我们建议研究志贺氏菌 III 型分泌效应器如何合作 抑制焦亡，从而使这种专业的胞浆内病原体能够在内部建立复制生态位 肠上皮细胞的胞浆。这些研究旨在显着扩大我们对 志贺氏菌和其他可能的肠道病原体如何抑制炎症小体。在完成拟议目标后， 预计所获得的知识可用于开发新颖的基于主机的 预防和治疗肠道感染的干预措施，鉴于新出现的肠道感染，这一需求尤为迫切 抗生素耐药性问题。