Evasion of Antigen Presentation by Vacuolar Pathogens

液泡病原体逃避抗原呈递

基本信息

批准号：
8223172
负责人：
Craig R. Roy
金额：
$ 44.67万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-01-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8223172
关键词：
Animal Model Antigen Presentation Bacteria Binding Bone Marrow Caspase-1 Cell surface Cells Complex Cytosol Data Defect Dendritic Cells Detection Endoplasmic Reticulum Eukaryotic Cell Event Extracellular Domain Genes Goals Health Host Defense Human Immune Immune response Immune system Immunity Immunologic Surveillance Infection Invaded Kinetics Learning Legionella pneumophila Leucine-Rich Repeat Link Lung Lymphocyte Lysosomes Mediating Microbe Molecular Mus Mutant Strains Mice Nucleotides Organelles Organism Pathway interactions Pattern Recognition Systems Pattern recognition receptor Play Process Production Protein Family Proteins Recruitment Activity Regulation Role Signal Pathway Signal Transduction Signaling Molecule Site System Toll-like receptors Transgenic Mice Type IV Secretion System Pathway Vacuole Vesicle adapter protein antimicrobial cell type combat cytokine insight interdisciplinary approach interest macrophage microbial microorganism antigen mutant novel pathogen prevent public health relevance receptor respiratory response uptake

项目摘要

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. PUBLIC HEALTH RELEVANCE: Intracellular pathogens represent a serious threat to human health, and to devise strategies to combat infections by these microbes a more detailed understanding of how the immune system responds to intracellular infection is needed. Thus, this project is focused on identifying molecular mechanisms that mediate host protection by investigating the role of immune surveillance pathways in generating a response against the intracellular pathogen Legionella pneumophila.

描述（由申请人提供）：本申请的重点是确定哺乳动物免疫系统如何产生一种反应，可保护对细胞内病原体的保护，该病原体在专门的细胞器内部复制。为了获得对这一过程的新洞察力，该项目的重点是确定宿主机制，这些机制可保护肺炎肺炎军团菌的感染。由衔接蛋白MyD88，RIP2，NLRC4和NAIP5控制的宿主模式识别系统已显示出触发对肺炎乳杆菌的先天免疫反应。该项目的总体目标是确定这些免疫监视系统产生的信号如何集成到功能反应中，以防止肺炎乳杆菌致命感染致命感染。该项目的目的是通过鉴定宿主细胞含有细胞内细菌，即接收到肺炎乳杆菌效应蛋白的宿主细胞来确定肺中的细胞特异性反应，该细胞通过点/ICM系统转移到细胞质中的宿主细胞，以及通过产生促促促炎性信号分子的宿主细胞，这些细胞对感染产生促炎信号分子。第二个目的是确定使用骨髓嵌合小鼠和转基因方法，确定宿主模式识别系统对肺乳杆菌的肺反应中的细胞特异性作用。第三个目的是确定炎性体的空间和时间激活如何通过研究通过NLRC4，Naip5和ASC激活的机制来限制肺炎乳杆菌的细胞内复制。这些数据将提供有关如何通过细胞内病原体接收和传播免疫信号的新细节。公共卫生相关性：细胞内病原体对人类健康构成了严重威胁，并制定策略来打击这些微生物的感染，对免疫系统如何应对细胞内感染有更详细的了解。因此，该项目的重点是通过研究免疫监测途径在产生针对肺炎内病原体的反应中的作用来鉴定介导宿主保护的分子机制。