Mechanism of M. tuberculosis Phagosome Maturation Arrest

结核分枝杆菌吞噬体成熟停滞的机制

基本信息

批准号：
7281579
负责人：
VOJO P DERETIC
金额：
$ 39.69万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-03-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7281579
关键词：
1-Phosphatidylinositol 3-Kinase ATP phosphohydrolase Abbreviations Acquired Immunodeficiency Syndrome Affect Antigen Presentation Autoantigens Bacillus (bacterium)Biogenesis Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Calmodulin Cell membrane Cells Cellular biology Chimeric Proteins Depth Detergents Development Disease Endoplasmic Reticulum Figs - dietary Foundations Funding GDP dissociation inhibitor GTP-Binding Proteins Generations Genus Mycobacterium Glycosylphosphatidylinositols Guanine Nucleotide Dissociation Inhibitors Human Hydrolase Infectious Agent Inositol Inositol 1,4,5-Trisphosphate Intervention Latex Bead Lead Link Lipids Literature Lysosomes Membrane Membrane Fusion Membrane Protein Traffic Multi-Drug Resistance Mycobacterium tuberculosis N-ethylmaleimide-sensitive protein National Institute of Allergy and Infectious Disease Numbers Opportunistic Infections Organelles Pathway interactions Phagocytes Phagolysosome Phagosomes Phosphatidylinositols Phosphotransferases Placement Population Process Proteins Proton-Translocating ATPases Research Personnel Rest Role SNAP receptor Screening procedure Signal Transduction Pathway Staging Transferrin Receptor Tuberculosis Zinc bactericide base biodefense bis(monoacylglyceryl)phosphate improved latent infection lipoarabinomannan macrophage mycobacterial novel pathogen phosphatidylinositol 3-phosphate phosphatidylinositol mannoside programs rab GTP-Binding Proteins rab5 GTP-Binding Proteins receptor size sphingosine 1-phosphate sphingosine kinase trafficking trans-Golgi Network

项目摘要

DESCRIPTION (provided by applicant): The ability of Mycobacterium tuberculosis to infect an extraordinary number of people, combined with the widespread emergence of multidrug resistance and opportunistic infections in AIDS, has lead to its placement on the NIAID list of biodefense and emerging infectious agents. M. tuberculosis persistence in human populations rests upon its ability to infect and survive in macrophages. Intracellular M. tuberculosis inhibits phagosomal maturation and resides in a pathogen-friendly phagosome escaping lysosomal bactericidal mechanisms and efficient antigen presentation. The long-term objectives of this project are to characterize mycobacterial products responsible for the M. tuberculosis phagosomal maturation block and identify the host cell membrane trafficking processes that are targeted by the mycobacterial factors. These phenomena have been linked to mycobacterial interference with membrane trafficking and organelle biogenesis processes controlled by host cell Rab GTPases. We hypothesize that M. tuberculosis interferes with specific Rab-interacting partners, including a Rab effector, phosphatidylinositol 3-kinase, that prepares phagosomes for tethering and fusion with other organelles. An integral part of this hypothesis is that M. tuberculosis lipids, which mimic mammalian phosphatidylinositols, affect organellar fusion and phagosomal maturation by interfering with phosphatidylinositol 3-kinase-dependent processes in the host cell. The specific aims are: 1. Identify M. tuberculosis lipid and protein products affecting phagosome maturation and characterize their mode of action. 2. Delineate the role of host cell membrane trafficking regulators including Rab5 effectors in M. tuberculosis phagosome maturation arrest. 3. Characterize novel, cell biology-based processes that can counteract M. tuberculosis phagosome maturation arrest. This three-prong approach will improve our understanding of a marquee pathogenic determinant of M. tuberculosis and provide a foundation for new interventions potentially combating both active disease and latent infection.

描述（由申请人提供）：结核分枝杆菌感染非凡人数的能力，再加上多药耐药性和艾滋病的机会性感染的广泛出现，导致了其在生物充足和新出现的感染者的NIAID清单上的位置。 M.人群中的结核病持续性取决于其在巨噬细胞中感染和生存的能力。细胞内的结核病抑制吞噬体成熟，并驻留在病原体友好的吞噬体中，逃避溶酶体杀菌机制和有效的抗原表现。该项目的长期目标是表征负责结核分枝杆菌吞噬体成熟块的分枝杆菌产品，并确定由分枝杆菌因素靶向的宿主细胞膜运输过程。这些现象与膜运输和细胞器生物发生过程受到宿主细胞RAB GTPase控制的细菌干扰有关。我们假设结核分枝杆菌会干扰特定的Rab互动伴侣，包括RAB效应子，磷脂酰肌醇3-激酶，该酶为吞噬体准备用于与其他细胞器的绑扎和融合。该假设的一个组成部分是结核分枝杆菌脂质（模拟哺乳动物磷脂酰肌醇）通过干扰宿主细胞中的磷脂酰肌醇3-激酶依赖性过程来影响细胞器融合和吞噬体成熟。具体目的是：1。鉴定影响吞噬体成熟并表征其作用方式的结核分枝杆菌脂质和蛋白质产物。 2。描述宿主细胞膜运输调节剂（包括RAB5效应子）在结核分枝杆菌吞噬体成熟停滞中的作用。 3。表征新颖的基于细胞生物学的过程，可以抵消结核分枝杆菌的吞噬体成熟。这种三个统计的方法将提高我们对结核分枝杆菌的官虫致病性决定因素的理解，并为潜在的干预措施与活性疾病和潜在感染作斗争为新的干预措施提供了基础。