Manipulation of epithelial cells by Shigella

描述(申请人提供)：志贺氏菌，NIAID B类病原体，每年导致约5.5亿腹泻或痢疾病例和110万人死亡。志贺氏菌感染的特征是诱导急性炎症，并伴随着中性粒细胞大量聚集到结肠，导致随后的大规模组织破坏。尽管宿主的反应令人印象深刻，志贺菌仍能在这种恶劣的环境中生存，主要是通过在结肠上皮细胞之间入侵和传播。志贺氏菌的存活主要是由于病原体通过~30个3型效应物的活性直接篡夺和调节宿主细胞的过程，这些蛋白是细菌通过其高度保守的3型分泌系统直接注入宿主细胞胞浆中的。志贺氏菌3型分泌系统在志贺氏菌致病的所有步骤中都是必不可少的，包括入侵宿主细胞、逃避吞噬小体、细胞内和细胞间扩散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器是如何使这种病原体逃避和抑制宿主固有免疫反应的。具体地说，我们建议确定3型效应器靶向的宿主细胞蛋白和/或过程，我们已经确定参与志贺氏菌吞噬小体逃逸和细胞到细胞的两个步骤，这两个步骤在志贺氏菌的发病机制中相对了解较少。这些研究应该证明关于细胞内细菌病原体传播的一般性见解。我们还建议鉴定宿主细胞蛋白，这些蛋白被志贺氏菌效应器泛素化并被降解，因为这些蛋白可能是信号通路中的关键元件，这些信号通路涉及正常诱导宿主天然免疫防御的正常作用，通常作用于对抗细菌病原体。通过实现和完成拟议的目标，我们预计将极大地扩大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固有免疫防御的理解。这些信息将有可能指导新疗法的开发，以预防和治疗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.