Regulation of Yersenia pestis virulence genes in response to host cell contact

描述（由申请方提供）：鼠疫耶尔森菌在感染过程中通过III型分泌系统（TTSS）将毒力因子从细菌细胞质转移到宿主免疫细胞中。该系统允许快速激活Yops的注射，Yops是一种蛋白质，其继续使吞噬作用和免疫识别失效，从而使细菌复制和疾病成为可能。TTSS是表达、分泌和易位孔的组装以及效应蛋白的注射的紧密协调的过程，所述效应蛋白对指示与宿主细胞接触的诱导迹象快速响应。这些事件的准确时间对于最佳性能至关重要，使鼠疫耶尔森氏菌能够从非常小的挑战剂量建立致命感染。我的实验室对效应蛋白的易位过程感兴趣，特别是在易位子如何插入质膜以及如何激活TTSS信号。在这项工作中，我们试图深入了解TTSS的激活，通过建立一个基本的理解的分子机制的抑制TTSS基因在没有宿主细胞接触，并通过识别基因，直接通过这种机制进行调节。建议的调查结果将提供初步的数据，我们可以建立一个程序，调查的TTSS在体内以及在体外，研究可能提供深入了解鼠疫耶尔森氏菌致病的分子机制的激活的分子事件。公共卫生相关性：本研究旨在探讨鼠疫致病菌鼠疫耶尔森氏菌III型分泌系统的调控机制。我们的目标是建立激活的TTSS在响应与宿主免疫细胞接触的分子机制，以研究这一过程中的作用，鼠疫的发展。

DESCRIPTION (provided by applicant): Yersinia pestis translocate virulence factors from the bacterial cytoplasm into host immune cells during infections through the Type III Secretion System (TTSS). This system allows for rapid activation of injection of Yops, proteins that go on to disable phagocytosis and immune recognition thereby enabling bacterial replication and disease. The TTSS is a tightly coordinated process of expression, assembly of secretion and translocation pores, and injection of effector proteins that responds rapidly to inducing signs indicating contact with a host cell. Accurate timing of these events is critical to optimum performance, allowing Yersinia pestis to establish lethal infections from very small challenge doses. My laboratory is interested in the process of translocation of effector proteins, specifically in how the translocon is inserted in the plasma membrane and how this signals activation of the TTSS. In this work, we seek to gain insight into the activation of the TTSS, by establishing a basic understanding of the molecular mechanism of repression of TTSS genes in the absence of host cell contact and through the identification of genes that are directly regulated through this mechanism. Results of the proposed investigations will provide preliminary data on which we can build a program that investigates molecular events of activation of the TTSS in vivo as well as in vitro, studies which may provide insight into the molecular mechanisms of Yersinia pestis pathogenesis. PUBLIC HEALTH RELEVANCE: This proposal investigates the mechanism of regulation of the type III secretion system in Yersinia pestis, the causative agent of plague. The goal is to establish the molecular mechanism of activation of the TTSS in response to contact with host immune cells in order to study the role of this process in the development of plague.