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

鼠疫耶尔森氏菌毒力基因响应宿主细胞接触的调节

• 批准号: 7739891
• 负责人: DEBORAH M ANDERSON
• 金额: $ 18.38万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-19 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739891
• 关键词: Affect; Bacteria; Bioinformatics; Biological Assay; Calcium; Cell membrane; Cells; Complex; Cytoplasm; Data; Development; Disease; Dose; Event; Genes; Goals; Immune; In Vitro; Infection; Injection of therapeutic agent; Investigation; Laboratories; Lead; Maps; Measures; Modeling; Molecular; Molecular Chaperones; Molecular Conformation; Pathogenesis; Performance; Plague; Point Mutation; Principal Investigator; Process; Proteins; Regulation; Regulatory Element; Repression; Role; Signal Transduction; System; Time; Transcriptional Activation; Type III Secretion System Pathway; Up-Regulation; Virulence; Virulence Factors; Work; Yersinia pestis; immune phagocytosis; in vivo; insight; interest; macrophage; novel; novel strategies; pathogen; prevent; programs; public health relevance; research study; response

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.

描述（由申请人提供）：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运到宿主免疫细胞中。该系统允许快速激活Yops注射，Yops蛋白质继续禁用吞噬和免疫识别，从而使细菌复制和疾病。TTSS是一个紧密协调的表达、分泌和易位孔的组装以及注射效应蛋白的过程，这些效应蛋白对指示与宿主细胞接触的诱导信号反应迅速。这些事件的准确时机对于最佳绩效至关重要，使鼠疫耶尔森菌能够从非常小的攻击剂量中建立致命感染。我的实验室对效应蛋白的易位过程很感兴趣，特别是易位子是如何插入质膜的，以及这是如何激活TTSS的信号。在这项工作中，我们试图通过在没有宿主细胞接触的情况下建立对TTSS基因抑制的分子机制的基本理解，并通过鉴定直接受该机制调节的基因，来深入了解TTSS的激活。这些研究的结果将为我们提供初步的数据，我们可以建立一个项目来研究TTSS在体内和体外激活的分子事件，这些研究可能为了解鼠疫耶尔森菌发病机制提供深入的分子机制。公共卫生相关性：本研究旨在探讨鼠疫病原体鼠疫耶尔森菌III型分泌系统的调控机制。目的是建立TTSS在与宿主免疫细胞接触时激活的分子机制，以研究这一过程在鼠疫发展中的作用。