Identifying genes essential for Legionella persistence and transmission

识别军团菌持续存在和传播所必需的基因

• 批准号: 8951725
• 负责人: Tamara O'Connor
• 金额: $ 24.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8951725
• 关键词: Adopted; Aerosols; Amoeba genus; Antibiotics; Automobile Driving; Bacteria; Biological Assay; Biological Models; Breathing; Clinical; Coculture Techniques; Disease; Disinfection; Environment; Epidemiology; Event; Evolution; Exhibits; Exposure to; Failure; Foundations; Genes; Genetic; Genome; Genomic Islands; Goals; Growth; Health; Hospitalization; Human; Incidence; Individual; Infection; Legionella; Legionella pneumophila; Legionellosis; Life; Marines; Methods; Molecular; Monitor; Organism; Parasites; Pathogenesis; Play; Pneumonia; Population; Procedures; Process; Proteins; Research; Resistance; Resources; Risk; Role; Severity of illness; Source; System; Training; Variant; Virulence; Virulence Factors; Water; Work; World Health; comparative; drinking water; exposed human population; feeding; fitness; functional genomics; insight; killings; macrophage; man; novel; novel strategies; pathogen; pathogenic bacteria; pressure; prevent; public health relevance; screening; transmission process; water quality

 DESCRIPTION (provided by applicant): Water-borne pathogens pose a serious threat to human health world-wide rendering water quality a fundamental determinant of the incidence and severity of disease. A critical factor in bacteria survival and proliferation in marine environments is the presence of grazing amoebae. These organisms feed on bacteria, playing a central role in restricting bacterial populations. However, many bacterial species have developed strategies to survive and replicate within amoebae. This has contributed to the emergence of human pathogens as these strategies can similarly be used by the bacterium to cause disease in humans. Amoebae also play an important role in the epidemiology of bacterial pathogens as their interaction enhances the pathogen's ability to cause an infection. Despite the importance of these interactions, little is known about the bacterial requirements for growth in amoebae. This severely limits our understanding of how these pathogens persist in environmental and man-made water sources and the factors that contribute to the incidence and severity of disease. The bacterial pathogen Legionella is present in over two thirds of potable water distribution systems. Exposure to this pathogen occurs through the inhalation of contaminated water aerosols which can result in life-threatening pneumonia. Legionella survives in potable water due to its ability to replicate within amoebae, which protects the bacterium from killing by water disinfection procedures. Confounding this problem, Legionella is able to grow in multiple types of amoebae. This is a key determinant of its survival in water reservoirs where amoebal populations are highly diverse. The goal of this research is to define bacterial requirements for growth in amoebae and the mechanisms responsible for the transmission of Legionella from environmental reservoirs to humans. To do this, high throughput phenotypic screening assays and functional genomics will be used to: 1) Systematically identify Legionella genes essential for replication in diverse amoebal hosts to define core virulence strategies commonly used in all hosts and auxiliary strategies that allow Legionella to adapt to variation between hosts; 2) Determine the conservation and functional importance of virulence genes across multiple environmental and clinical isolates to assess the utility of their encoded proteins as targets against a broad spectrum of Legionellae. These studies will provide a foundation for developing more effecting strategies for eliminating bacteria from water resources to reduce the risk of infection and unique insight into Legionella pathogenesis that will be instrumental in developing novel strategies for treating disease.

 描述（由申请人提供）：水传播病原体对全世界人类健康构成严重威胁，使得水质成为疾病发生率和严重程度的根本决定因素。海洋环境中细菌生存和增殖的一个关键因素是食草变形虫的存在。这些生物体以细菌为食，在限制细菌数量方面发挥着核心作用。然而，许多细菌物种已经发展出在变形虫内生存和复制的策略。这导致了人类病原体的出现，因为细菌同样可以使用这些策略来引起人类疾病。变形虫在细菌病原体的流行病学中也发挥着重要作用，因为它们的相互作用增强了病原体引起感染的能力。尽管这些相互作用很重要，但人们对阿米巴原虫生长的细菌需求知之甚少。这严重限制了我们对这些病原体如何在环境和人造水源中持续存在以及导致疾病发生和严重程度的因素的理解。 细菌病原体军团菌存在于超过三分之二的饮用水分配系统中。通过吸入受污染的水气溶胶而接触这种病原体，这可能导致危及生命的肺炎。军团菌能够在饮用水中存活，因为它能够在变形虫内复制，从而保护细菌不被水消毒程序杀死。与这个问题混淆的是，军团菌能够在多种变形虫中生长。这是其在变形虫种群高度多样化的水库中生存的关键决定因素。这项研究的目的是确定阿米巴原虫生长的细菌需求以及军团菌从环境宿主传播到人类的机制。为此，高通量表型筛选试验和功能基因组学将用于：1）系统地鉴定军团菌在不同变形虫宿主中复制所必需的基因，以确定所有宿主中常用的核心毒力策略和允许军团菌适应宿主之间差异的辅助策略； 2) 确定多个环境和临床分离株中毒力基因的保守性和功能重要性，以评估其编码蛋白的效用 作为针对广泛的军团菌的目标。这些研究将为制定更有效的策略奠定基础，以消除水资源中的细菌，从而降低感染风险，并对军团菌发病机制有独特的见解，这将有助于制定治疗疾病的新策略。