Evasion of Antigen Presentation by Vacuolar Pathogens

描述(申请人提供)：本申请的重点是确定哺乳动物免疫系统如何产生反应，以提供对在特殊细胞器内复制的细胞内病原体的保护。为了对这一过程有新的见解，该项目专注于确定提供保护免受细胞内病原体嗜肺军团菌感染的宿主机制。宿主模式识别系统由接合蛋白MyD88、RIP2、NLRC4和Naip5控制，已被证明能触发对嗜肺乳杆菌的先天免疫反应。该项目的总体目标是确定如何将这些免疫监测系统产生的信号整合到功能反应中，以防止嗜肺乳杆菌的致命性感染。该项目的目的是通过识别含有细胞内细菌的宿主细胞、通过Dot/ICM系统转位到胞浆中的嗜肺乳杆菌效应蛋白的宿主细胞以及产生致炎信号分子的宿主细胞来确定肺中的细胞特异性反应。第二个目的是利用骨髓嵌合小鼠和转基因方法来确定宿主模式识别系统在肺炎链球菌肺部反应中的细胞特异性作用。第三个目的是通过研究通过NLRC4、Naip5和ASC激活caspase-1的机制来确定炎症体的空间和时间激活如何限制嗜肺乳杆菌的细胞内复制。这些数据将提供有关免疫信号在细胞内病原体感染期间如何接收和传播的新细节。

DESCRIPTION (provided by applicant): The focus of this application is to determine how the mammalian immune system generates a response that provides protection against intracellular pathogens that replicate inside of specialized organelles. To gain novel insight into this process, this project has focused on determining the host mechanisms that provide protection against infection by the intracellular pathogen Legionella pneumophila. Host pattern recognition system controlled by the adapter proteins MyD88, Rip2, NLRC4, and Naip5 have been shown to trigger innate immune responses to L. pneumophila. The overall goal of this project is to determine how signals generated from these immune surveillance systems are integrated into a functional response that prevents lethal infection by L. pneumophila. The aims of this project are to determine cell-specific responses in the lung by identifying host cells contain intracellular bacteria, host cells that have received L. pneumophila effector proteins translocated into the cytosol by the Dot/Icm system, and host cells that are producing proinflammatory signaling molecules in response to infection. The second aim is to determine the cell- specific roles for host pattern recognition systems in the pulmonary response to L. pneumophila using bone marrow chimeric mice and transgenic approaches. The third aim is to determine how spatial and temporal activation of the inflammasome restricts intracellular replication of L. pneumophila by investigating the mechanisms that underlie caspase-1 activation through NLRC4, Naip5 and ASC. These data will provide new details on how immune signals are received and propagated during infection by an intracellular pathogen.