Mycobacterial Genes Responsible for Regulating Autophagy

负责调节自噬的分枝杆菌基因

• 批准号: 8175674
• 负责人: Sunhee Lee
• 金额: $ 23.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8175674
• 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; success; trafficking; vaccine candidate; vaccine efficacy

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起重要作用。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断自噬体与溶酶体的融合以逃避降解，或利用这些囊泡中的营养物质。已经证明，刺激巨噬细胞中的自噬途径导致分枝杆菌吞噬体成熟为吞噬溶酶体，其可以克服结核分枝杆菌施加的运输阻断。因此，诱导自噬抑制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，以确保受感染的巨噬细胞内的生存。这些毒力因子的鉴定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应答结果的机制。通过用粘粒文库转化的分枝杆菌的功能获得筛选，我们能够鉴定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，并评估其对分枝杆菌生存和免疫的作用。增加了对M.结核感染诱导的自噬可能导致新的和有希望的抗结核治疗。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TB疫苗中具有重要应用。 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，它可以增强获得性免疫的启动。本研究结果对提高卡介苗的免疫效果和开发新型结核病候选疫苗具有重要意义。