Role of the T3SS effector protein IcsB in Shigella flexneri infection

项目总结/摘要 福氏志贺菌是一种引起志贺菌病的人类病原体，志贺菌病是一种严重的肠道疾病。S.弗莱克斯纳入侵 结肠粘膜，在那里它在上皮细胞的胞质溶胶中复制并在细胞间传播。这 传播过程依赖于细胞溶质肌动蛋白为基础的运动和膜突起的形成， 投射到相邻的细胞中。这些膜突起的分解导致形成双 膜空泡（DMV），细菌随后从中逃逸，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，S。弗氏三型分泌系统 在传播过程的多个阶段，包括突起分辨率和双折射， 膜DMV逃逸。我最近已经表明，T3 SS效应蛋白IcsB有助于S。福氏 通过促进迅速有效地逃离DMV来传播。在这里，我建议确定 ICsB促进DMV逃逸的机制（Aim 1）及其与我们最近研究的发病机制的相关性。 建立人志贺氏菌病幼兔模型（目的2）。我的中心假设是ICSB是一个关键的 操纵宿主Rho GTP酶以促进DMV迅速和有效逃逸的毒力因子。自S. 福氏播散是发病机制的关键决定因素，我的工作可能揭示新的治疗方法， 干预治疗人志贺氏菌病。

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.