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Mycobacterial Genes Responsible for Regulating Autophagy

负责调节自噬的分枝杆菌基因

基本信息

批准号：
8264512
负责人：
Sunhee Lee
金额：
$ 19.63万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-15 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8264512
关键词：
Affect Autophagocytosis Autophagosome Bacillus (bacterium)Bacteria Biogenesis Calmette-Guerin Bacillus Cells Cessation of life Communicable Diseases Complex Cosmids Data Development Encapsulated Ensure Environment Extreme drug resistant tuberculosis Future Genes Genetic Determinism Genomics Genus Mycobacterium Goals Grant HIV Host Defense Human Immune Immune response Immunity Immunologic Memory Infection Integration Host Factors Knock-out Knowledge Lead Libraries Lysosomes Mediating Microbe Molecular Multi-Drug Resistance Mutate Mycobacterium Infections Mycobacterium bovis Mycobacterium smegmatis Mycobacterium tuberculosis Natural Immunity Nutrient Organelles Outcome Pathway interactions Peptides Phagocytes Phagolysosome Phagosomes Pharmacotherapy Physiological Population Proteins Regulation Research Role Screening procedure Signal Pathway Small Interfering RNA Testing Therapeutic Therapeutic Intervention Tuberculosis Tuberculosis Vaccines Vaccine Therapy Vaccines Vacuole Vesicle Viral Virulence Factors Virulent adaptive immunity gain of function genome-wide global health high throughput screening improved latent infection macrophage microbial mutant mycobacterial pathogen prophylactic public health relevance success trafficking vaccine candidate vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): Autophagy, an important host defense pathway, has an essential role in both innate and adaptive immunity. However, many microbes have evolved mechanisms to evade, subvert, or exploit autophagy. Bacterial and viral pathogens can block autophagosome fusion with lysosomes to evade degradation, or utilize nutrients in such vesicles. It has been demonstrated that stimulation of autophagic pathways in macrophages causes mycobacterial phagosomes to mature into phagolysosomes, which can overcome the trafficking block imposed by Mycobacterium tuberculosis. Thus, induction of autophagy suppressed intracellular survival of mycobacteria. We hypothesize that mycobacterial virulence factors mediate autophagy evasion in order to ensure survival within the infected macrophages. The identification and inhibition of such virulence factors will allow us to understand the mechanisms by which autophagy affects the outcome of host-microbe interactions and the immune responses. Through gain-of-function screening of mycobacteria transformed with a cosmid library, we were able to identify two chromosomal regions responsible for manipulating mycobacterial infection- induced autophagy. We propose to study these two genomic regions and evaluate their role on mycobacterial survival and immunity. Increased knowledge of M. tuberculosis infection-induced autophagy may lead to new and promising therapeutics against tuberculosis. Additionally, the pro-autophagic mutants generated in this study may have significant application in the development of effective, safe and persistent TB vaccines. PUBLIC HEALTH RELEVANCE: We propose to study autophagy-regulating genes of Mycobacterium tuberculosis that enhances priming of adaptive immunity. The results of the study will be useful for improving the vaccine efficacy of BCG and developing noble TB vaccine candidates.

描述(由申请人提供)：自噬是一种重要的宿主防御途径，在先天免疫和获得性免疫中都具有重要作用。然而，许多微生物已经进化出逃避、颠覆或利用自噬的机制。细菌和病毒病原体可以阻止自噬小体与溶酶体的融合，以逃避降解，或利用此类小泡中的营养物质。已有研究表明，刺激巨噬细胞中的自噬途径可使分枝杆菌吞噬小体成熟为吞噬小体，从而克服结核分枝杆菌对巨噬细胞运输的阻碍。因此，自噬的诱导抑制了分枝杆菌在细胞内的存活。我们假设分枝杆菌毒力因子介导自噬逃避，以确保在受感染的巨噬细胞内存活。这些毒力因子的识别和抑制将使我们能够理解自噬影响宿主-微生物相互作用和免疫反应的机制。通过对粘粒文库转化的分枝杆菌进行功能增益筛选，我们能够识别出两个负责操纵分枝杆菌感染诱导的自噬的染色体区域。我们建议研究这两个基因组区域，并评估它们在分枝杆菌生存和免疫中的作用。增加对结核分枝杆菌感染诱导的自噬的了解可能会导致治疗结核病的新的和有前途的疗法。此外，本研究中产生的自噬前突变体可能在开发有效、安全和持久的结核病疫苗方面具有重要应用价值。公共卫生相关性：我们建议研究结核分枝杆菌的自噬调节基因，以增强适应性免疫的启动。本研究结果将有助于提高卡介苗的疫苗效力，开发高能结核疫苗候选疫苗。