Mechanism of M. tuberculosis Phagosome Maturation Arrest

结核分枝杆菌吞噬体成熟停滞的机制

• 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
• 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

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）：结核分枝杆菌感染大量人群的能力，加上艾滋病中广泛出现的多药耐药性和机会性感染，导致其被列入NIAID生物防御和新兴传染源名单。M.结核病在人群中的持续存在取决于其感染巨噬细胞并在巨噬细胞中存活的能力。胞内M.结核病抑制吞噬体成熟，并存在于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呈递。该项目的长期目标是表征导致M。结核吞噬体成熟阻断和鉴定分枝杆菌因子靶向的宿主细胞膜运输过程。这些现象与分枝杆菌干扰宿主细胞Rab GTP酶控制的膜运输和细胞器生物合成过程有关。我们假设M.结核病干扰特定的Rab相互作用的伙伴，包括Rab效应，磷脂酰肌醇3-激酶，准备吞噬体与其他细胞器的束缚和融合。这个假设的一个组成部分是M。模拟哺乳动物磷脂酰肌醇的结核脂质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。具体目标是：1.识别M。结核脂质和蛋白质产物影响吞噬体成熟，并表征其作用模式。2.阐明宿主细胞膜运输调节因子包括Rab 5效应子在M.结核病吞噬体成熟停滞。3.表征可以对抗M的基于细胞生物学的新型过程。结核病吞噬体成熟停滞。这种三管齐下的方法将提高我们对M的一个重要致病决定因素的理解。结核病和提供新的干预措施可能打击活动性疾病和潜伏感染的基础。