Manipulation of epithelial cells by Shigella

描述（由申请人提供）：志贺氏菌，NIAID B类病原体，每年导致约5.5亿例腹泻或痢疾，110万人死亡。志贺氏菌感染的特点是诱导急性炎症，并伴有大量中性粒细胞聚集到结肠，导致随后的大量组织破坏。尽管宿主有这种令人印象深刻的反应，志贺氏菌在这种恶劣的环境中存活下来，主要是通过入侵和在结肠上皮细胞之间扩散。志贺氏菌的存活主要是由于这种病原体能够通过30种3型效应物（细菌通过其高度保守的3型分泌系统直接注射到宿主细胞质中的蛋白质）的活性直接篡位和调节宿主细胞的过程。志贺氏菌3型分泌系统在志贺氏菌发病的所有步骤中都是必不可少的，包括它们入侵宿主细胞、逃离吞噬体、细胞内和细胞间传播以及抑制促炎细胞因子的产生。我们研究的总体目标是了解志贺氏菌效应物如何使这种病原体逃避和抑制宿主的先天免疫反应。具体来说，我们建议确定宿主细胞蛋白和3型效应物靶向的过程，我们已经确定这些蛋白和过程涉及志贺菌吞噬体逃逸和细胞-细胞，这是志贺菌发病机制中相对知之甚少的两个步骤。这些研究应该证明关于细胞内细菌病原体传播的一般见解。我们还建议鉴定被志贺氏菌效应物降解的定向泛素化宿主细胞蛋白，因为这些蛋白可能是参与正常诱导宿主先天免疫防御的信号通路的关键元件，通常作用于对抗细菌病原体。通过执行和完成提出的目标，我们期望大大扩展我们对志贺氏菌和其他细胞内病原体如何操纵宿主细胞过程以逃避宿主先天免疫防御的理解。这一信息将有可能指导开发新的治疗方法，以预防和治疗由志贺氏菌和其他细菌病原体引起的感染。

DESCRIPTION (provided by applicant): Shigella, NIAID category B pathogens, cause ~550 million cases of diarrhea or dysentery and 1.1 million deaths each year. Shigella infections are characterized by the induction of acute inflammation associated with a massive recruitment of neutrophils to the colon resulting in subsequent massive tissue destruction. Despite this impressive host response, Shigella survive in this harsh environment, primarily by invading and spreading between colonic epithelial cells. Shigella survival is primarily due to the ability of ths pathogen to directly usurp and regulate host cell processes through the activity of ~30 type 3 effectors, proteins that the bacteria directly injects into the host cell cytosol through its highl conserved type 3 secretion system. The Shigella type 3 secretion system is essential for all steps in Shigella pathogenesis including their invasion of host cells, escape from the phagosome, intracellular and intercellular spread and inhibition of the production of pro-inflammatory cytokines. The overall goal of our research is to understand how Shigella effectors enable this pathogen to evade and suppress host innate immune responses. Specifically we propose to determine the host cell proteins and or processes targeted by type 3 effectors that we have established to be involved in Shigella phagosomal escape and cell-to-cell, two steps in Shigella pathogenesis that are relatively poorly understood. These studies should prove general insights regarding the spread of intracellular bacterial pathogens. We also propose to identify host cell proteins directed ubiquitinated and targeted for degradation by Shigella effectors as these proteins are likely key elements in signaling pathways involved in normally inducing host innate immune defenses that normally act to combat bacterial pathogens. By performing and completing the proposed aims, we expect to greatly expand our understanding of how Shigella and other intracellular pathogens manipulate host cell processes in order to evade host innate immune defenses. This information will have the potential to guide the development of novel therapeutics to prevent and treat infections caused by Shigella and other bacterial pathogens.