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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要 Shigella flexneri是一种人类病原体，会导致志氏病，这是一种严重的腹泻病。 S. Flexneri入侵结肠粘膜在上皮细胞的细胞质中复制并从细胞传播到细胞。这传播过程依赖于基于胞质肌动蛋白的运动和形成膜突起的过程投射到相邻的细胞中。这些膜突起的分辨率导致双重形成膜液泡（DMVS），随后细菌从中逃脱，从而获得了进入相邻细胞的胞质室。我们的实验室表明S. flexneri三型分泌系统（T3SS）在传播过程的多个阶段需要（包括突出分辨率和双重）膜DMV逃脱。我最近表明，T3SS效应蛋白ICSB有助于S. flexneri 通过促进DMV迅速而有效的逃脱来传播。在这里，我建议确定 ICSB促进DMV逃逸（AIM 1）及其与我们最近的发病机理相关的机制发展的人类志氏病的婴儿兔模型（AIM 2）。我的中心假设是ICSB是关键操纵宿主Rho GTP酶以促进迅速有效的DMV逃脱的毒力因子。自S. Flexneri传播是发病机理的关键决定因素，我的工作可能揭示了新的治疗性干预治疗人类志硬病的干预措施。