Role of the T3SS effector protein IcsB in Shigella flexneri infection

T3SS效应蛋白IcsB在福氏志贺菌感染中的作用

• 批准号: 10001964
• 负责人: Erin A Weddle
• 金额: $ 3.42万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001964
• 关键词: Actins; Acyltransferase; Animal Model; Bacteria; Biochemical; Bioinformatics; Cell Line; Cell physiology; Cells; Cessation of life; Colon; Confocal Microscopy; Cysteine; Cytosol; Defect; Disease; Distal; Epithelial Cells; Genetic; Goals; Histidine; Human; Individual; Infant; Infection; Inflammation; Intestinal Mucosa; Intestines; Invaded; Lead; Mass Spectrum Analysis; Measures; Mediating; Membrane; Modification; Molecular; Mucous Membrane; Multi-Drug Resistance; Mutation; Needles; Oryctolagus cuniculus; Outcome; Pathogenesis; Pathology; Peptide Hydrolases; Prevention; Process; Proteins; RNA Interference; Research Proposals; Resolution; Role; Shigella; Shigella Infections; Shigella flexneri; System; Testing; Therapeutic Intervention; Vaccines; Vacuole; Virulence Factors; Work; base; cell motility; diarrheal disease; human model; human pathogen; insight; mutant; novel; novel therapeutic intervention; pathogen; recruit; rho GTP-Binding Proteins; time use

PROJECT SUMMARY/ABSTRACT Shigella flexneri is a human pathogen that causes shigellosis, a severe diarrheal disease. S. flexneri invades the colonic mucosa where it replicates in the cytosol of epithelial cells and spreads from cell to cell. This dissemination process relies on cytosolic actin-based motility and formation of membrane protrusions that project into adjacent cells. The resolution of these membrane protrusions leads to formation of double membrane vacuoles (DMVs), from which the bacteria subsequently escape, thereby gaining access to the cytosolic compartment of adjacent cells. Our lab has shown that the S. flexneri type three secretion system (T3SS) is required at multiple stages of the dissemination process, including protrusion resolution and double membrane DMV escape. I have shown recently that the T3SS effector protein IcsB contributes to S. flexneri dissemination by promoting prompt and efficient escape from DMVs. Here, I propose to determine the mechanism by which IcsB facilitates DMV escape (Aim 1) and its relevance to pathogenesis in our recently developed infant rabbit model of human shigellosis (Aim 2). My central hypothesis is that IcsB is a critical virulence factor that manipulates host Rho GTPases to promote prompt and efficient DMV escape. Since S. flexneri dissemination is a critical determinant of pathogenesis, my work may reveal novel therapeutic intervention for treating human shigellosis.

项目概要/摘要 福氏志贺氏菌是一种引起志贺氏菌病（一种严重腹泻病）的人类病原体。弗氏链球菌入侵 它在结肠粘膜上皮细胞的胞浆中复制并从一个细胞传播到另一个细胞。这 传播过程依赖于基于细胞质肌动蛋白的运动和膜突起的形成 投影到相邻的单元格中。这些膜突起的分解导致形成双 膜液泡（DMV），细菌随后从中逃脱，从而获得进入 相邻细胞的胞质区室。我们的实验室已经证明福氏链霉菌三型分泌系统 （T3SS）在传播过程的多个阶段都需要，包括突出分辨率和双 膜DMV逃逸。我最近证明 T3SS 效应蛋白 IcsB 对福氏链霉菌有贡献 通过促进迅速有效地逃离 DMV 进行传播。在此，我建议确定 IcsB 促进 DMV 逃逸的机制（目标 1）及其与我们最近的发病机制的相关性 开发了人类志贺氏菌病的幼兔模型（目标 2）。我的中心假设是 IcsB 是一个关键的 操纵宿主 Rho GTPases 促进迅速有效的 DMV 逃逸的毒力因子。自从S。 福氏菌传播是发病机制的关键决定因素，我的工作可能会揭示新的治疗方法 治疗人类志贺氏菌病的干预措施。