Molecular analysis of the interaction between Legionella pneumophila and its

描述（由申请方提供）：军团病是一种肺炎，由含有细菌病原体嗜肺军团菌的雾化水源引起，通过在肺巨噬细胞内复制引发疾病。虽然这种细菌能够在细胞外生长，但人们认为它在环境中主要在变形虫体内复制。一旦进入宿主细胞，军团菌就有能力调节宿主细胞的过程，以形成一个由内质网包围的区室，细菌在其中驻留和复制。这种隔室的形成，称为军团菌含嗜酸性粒细胞（LCV），需要存在细菌Dot/Icm系统，即IV型分泌系统（T4 SS）。许多研究已经强调了T4 SS在调节宿主内吞和分泌途径以形成LCV中的重要性，但是对于早期分泌装置之外的可以调节细胞内生长的宿主因子知之甚少。大规模RNAi筛选表明，参与细胞周期控制或蛋白质合成起始的宿主蛋白质的耗尽导致细菌的细胞内生长增强，这与宿主细胞周期的破坏刺激细胞内复制的模型一致。这个奖学金计划的目的是了解宿主细胞周期控制和翻译起始因子如何促进细菌增殖。进行实验以：1）确定L. pneumophila能够控制宿主细胞周期以刺激细胞内复制;和2）确定L.嗜肺菌易位蛋白通过调节宿主翻译和细胞周期网络来刺激细菌生长。从所提出的实验中获得的结果将允许确定为什么细胞周期中断刺激L。嗜肺菌胞内生长，目的是确定微生物是否优先在终末分化细胞中复制。

DESCRIPTION (provided by applicant): Legionnaire's disease is a pneumonia that results from aerosolized water sources containing the bacterial pathogen Legionella pneumophila, which initiates disease by replicating within lung macrophages. Although the bacterium is capable of growing extracellularly, it is thought that in the environment it primarily replicates within amoebae. Once inside host cells, Legionella has the capacity to modulate host cell processes in order to form a compartment surrounded by endoplasmic reticulum, where the bacteria resides and replicates. Formation of this compartment, known as the Legionella Containing Vacuole (LCV), requires the presence of the bacterial Dot/Icm system, a Type IV Secretion System (T4SS). Numerous studies have highlighted the importance of the T4SS in modulating the host endocytic and secretory pathways to form the LCV, but little is known about host factors outside of the early secretory apparatus that could modulate intracellular growth. A large-scale RNAi screen demonstrated that depletion of host proteins involved in cell cycle control or initiation of protein synthesis resulted in enhanced intracellular growth of the bacterium, consistent with the model that disruption of the host cell cycle stimulates intracellula replication. The goal of this fellowship proposal is to understand how host factors involved in cel cycle control and translational initiation contribute to bacterial proliferation. Experiments will e performed to: 1) determine if L. pneumophila is able to control the host cell cycle to stimulate intracellular replication; and 2) determine if L. pneumophila translocated proteins play are role i stimulating bacteria growth by modulating host translation and cell cycle networks. The results acquired from the proposed experiments will allow the determination of why cell cycle disruption stimulates L. pneumophila intracellular growth, with the intention of determining if the microorganism replicates preferentially in terminally differentiated cells.