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，在先天免疫和适应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、破坏或利用自噬的机制。细菌和病毒病原体可以阻止自噬体与溶酶体融合以逃避降解，或利用此类囊泡中的营养物质。已经证明，刺激巨噬细胞中的自噬途径会导致分枝杆菌吞噬体成熟为吞噬溶酶体，从而克服结核分枝杆菌施加的运输障碍。因此，自噬的诱导抑制了分枝杆菌的细胞内存活。我们假设分枝杆菌毒力因子介导自噬逃避，以确保受感染巨噬细胞内的存活。这些毒力因子的识别和抑制将使我们能够了解自噬影响宿主-微生物相互作用和免疫反应结果的机制。通过对粘粒文库转化的分枝杆菌进行功能获得性筛选，我们能够鉴定出负责操纵分枝杆菌感染诱导的自噬的两个染色体区域。我们建议研究这两个基因组区域并评估它们对分枝杆菌存活和免疫的作用。对结核分枝杆菌感染诱导的自噬了解的增加可能会带来新的、有前途的结核病治疗方法。此外，本研究中产生的促自噬突变体可能在开发有效、安全和持久的结核疫苗方面具有重要应用。公共健康相关性：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。该研究结果将有助于提高卡介苗的疫苗功效和开发优良的结核病候选疫苗。