Analysis of L. Pneumophilia Virulence Regulation

嗜肺军团菌毒力调控分析

基本信息

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
项目类别：
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

项目摘要

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.

微生物的标志是能够改变其生理学以耐受或利用当地条件的能力。适应对于病原体至关重要，因为这些微生物在它们之间循环时会面对不同的环境定植和传播的时期。作为阐明微生物影响的实验模型发病机理的分化，我们分析了吞噬细胞的革兰氏阴性细胞内病原体。我们在这里检验以下假设，即，为了在人肺及其水生储存库中繁殖，肺炎L. pneumophila在A中表达倒数模式至少两组不同的生化途径：一种用于促进吞噬细胞复制的生化途径液泡和另一个刺激宿主细胞之间的传播。假设其leta/s二 - 组件调节系统旨在授予病原体的多功能性。经过利用管理肺炎乳杆菌分化的调节电路的知识，缺乏的突变体调节剂Flia，Leta，Lets或CSRA或苏氨酸tranporter PHTA，该基因组序列费城，巴黎和镜头菌株，生物信息学和微阵列技术以及分子和遗传功能的测定，使病原体的机制在细胞内复制之间循环和可以阐明传输。生命周期每个阶段至关重要的分子特征可以告知剂的设计从受污染的水供应和从感染的肺。这些研究将共同提供一个框架来研究生化途径配备细胞内微生物从环境中出现，以引起机会性感染。因此，此处确定的概念和途径还可以指导和管理不太易加的细胞内病原体，例如分枝杆菌，衣原体，弗朗西斯氏菌和柯西拉物种。