Analysis of L. Pneumophilia Virulence Regulation

微生物的一个特点是能够改变自己的生理机能，以耐受或利用当地的条件。调适 对病原体至关重要，因为这些微生物在不同的环境中循环 殖民期和传播期。作为一个实验模型来阐明微生物的影响 在病机辨证上，我们分析了一种革兰氏阴性杆菌的细胞内吞噬细胞。在这里我们 检验这样一种假设，即嗜肺性乳杆菌为了在人的肺和它的水生水库中茁壮成长，在一种 至少有两套不同的生化途径：一种是促进吞噬细胞复制 一种是空泡，另一种是刺激宿主细胞之间的传递。假设它的乐塔/S两个- 为了赋予病原体通用性而设计的成分调控系统也将进行测试。通过 利用控制嗜肺乳杆菌分化的调控电路的知识，缺乏 调节子FliA、Leta、Lets或CSRA，或苏氨酸转运蛋白PhtA，基因组序列 费城、巴黎和兰斯菌株，生物信息学和微阵列技术，以及分子和遗传学 功能分析，使病原体在细胞内复制和循环之间循环的机制 传播可以被阐明。对生命周期每个阶段至关重要的分子特征可以告诉我们 从受污染的水源和环境中根除这种机会性病原体的制剂设计 肺部感染。总而言之，这些研究将提供一个框架，以研究 使细胞内的微生物能够从环境中出现，从而引起机会性感染。因此， 这里确定的概念和途径也可以指导对较难处理的细胞内的研究和管理 病原体，如分枝杆菌、衣原体、方济氏菌和柯克斯体。

A hallmark of microbes is the ability to alter their physiology to tolerate or exploit local conditions. Adaptation is crucial for pathogens, since these microorganisms confront distinct environments as they cycle between periods of colonization and transmission. As an experimental model to elucidate the impact of microbial differentiation on pathogenesis, we analyze a gram-negative intracellular pathogen of phagocytes. Here we test the hypothesis that, to thrive in the human lung and its aquatic reservoir, L. pneumophila expresses in a reciprocal pattern at least two distinct sets of biochemical pathways: one to promote replication in phagocyte vacuoles and the other to stimulate transmission between host cells. The hypothesis that its LetA/S two- component regulatory system is designed to confer versatility to the pathogen will also be tested. By exploiting knowledge of the regulatory circuit that governs L. pneumophila differentiation, mutants that lack the regulators FliA, LetA, LetS, or CsrA, or the threonine tranporter PhtA, the genome sequences of the Philadelphia, Paris and Lens strains, bioinformatic and microarray technology, and molecular and genetic assays of function, mechanisms that equip pathogens to cycle between intracellular replication and transmission can be elucidated. The molecular features critical to each stage of the life cycle can inform design of agents to eradicate this opportunistic pathogen from contaminated water supplies and from the infected lung. Together, these studies will provide a framework to investigate the biochemical pathways that equip intracellular microbes to emerge from the environment to cause opportunistic infections. Thus, concepts and pathways identified here can also guide studies and management of less tractable intracellular pathogens such as the Mycobacteria, Chlamydia, Francisella, and Coxiella species.