Analysis of L. Pneumophilia Virulence Regulation

嗜肺军团菌毒力调控分析

• 批准号: 7846541
• 负责人: MICHELE Somes SWANSON
• 金额: $ 1.58万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846541
• 关键词: Adherence; Algorithms; Amoeba genus; Bacteria; Base Sequence; Binding Sites; Biochemical; Biochemical Pathway; Bioinformatics; Biological Assay; Candidate Disease Gene; Cells; Chlamydia; Coxiella; Dot Immunoblotting; Enabling Factors; Engineering; Environment; Experimental Models; Francisella; Genes; Genetic; Genome; Genomics; Genus Mycobacterium; Goals; Human; Knowledge; Life; Life Cycle Stages; Lung; Mediating; Microarray Analysis; Microbe; Molecular; Molecular Genetics; Molecular Profiling; Opportunistic Infections; Paris, France; Pathogenesis; Pathway interactions; Pattern; Phagocytes; Phagosomes; Phase; Phenotype; Philadelphia; Physiology; Pigments; Production; RNA; Regulation; Regulon; Research; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Sigma Factor; Signal Transduction; Staging; Stress; System; Testing; Threonine; Vacuole; Virulence; Virulent; Water; Water Supply; cell motility; cytotoxicity; design; genome sequencing; lens; macrophage; member; microbial; microorganism; mutant; novel; pathogen; trafficking; trait; transmission process

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.

微生物的一个标志是能够改变其生理机能以适应或利用当地条件。适应 是至关重要的病原体，因为这些微生物面临不同的环境，因为它们之间的循环， 殖民和传播的时期。作为一个实验模型，以阐明微生物的影响 在发病机制上的分化，我们分析了吞噬细胞的革兰氏阴性细胞内病原体。这里我们 为了在人类肺部及其水生水库中茁壮成长，L. pneumophila在一个 相互模式至少有两套不同的生化途径：一种促进吞噬细胞的复制 液泡和其他刺激宿主细胞之间的传输。假设其LetA/S为两个- 还将测试旨在赋予病原体多功能性的组分调节系统。通过 利用控制L的调节回路的知识。嗜肺菌分化，缺乏 调节因子FliA、LetA、LetS或CsrA，或苏氨酸转运蛋白PhtA，其基因组序列 费城、巴黎和透镜菌株，生物信息学和微阵列技术，以及分子和遗传学 功能测定，使病原体在细胞内复制和 可以解释传输。对生命周期的每个阶段至关重要的分子特征可以告知 设计药剂以从受污染的水源中和 肺部感染总之，这些研究将提供一个框架，以调查生化途径， 使细胞内的微生物从环境中出现，引起机会性感染。因此，在本发明中， 这里确定的概念和途径也可以指导研究和管理不易处理的细胞内 病原体如分枝杆菌属、衣原体属、弗朗西斯菌属和柯克斯菌属。