Virulence Regulation by the Mycobacterium Tuberculosis Proteasome

结核分枝杆菌蛋白酶体的毒力调节

• 批准号: 7670280
• 负责人: Katerina Heran Darwin
• 金额: $ 42.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7670280
• 关键词: ATP phosphohydrolase; Age; Antibiotics; Attenuated; Bacteria; Biology; Cell physiology; Complex; Contracts; Disease; Drug resistance; Enzymes; Eukaryota; Expectancy; Future; Gene Expression; Genes; Genus Mycobacterium; Goals; Growth; HIV Infections; Host Defense; Housekeeping; Immunosuppressive Agents; In Vitro; Intermediate resistance; Microarray Analysis; Molecular Chaperones; Mus; Mutate; Mutation; Mycobacterium tuberculosis; Nitric Oxide; Nitrogen; Pathogenesis; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Predisposition; Prevalence; Production; Proteins; Proteolysis; Public Health; Regulation; Resistance; Shapes; Stress; Testing; Toxic effect; Tuberculosis; Virulence; combat; in vivo; killings; macrophage; multicatalytic endopeptidase complex; mutant; protein degradation; resistant strain; tuberculosis treatment

DESCRIPTION (provided by applicant): Tuberculosis kills about 2 million people globally every year. A key defense against Mycobacterium tuberculosis (Mtb) infections is the production of nitric oxide (NO) by macrophages. Although NO controls Mtb growth, it rarely sterilizes the bacterium from the host. Therefore, it is likely that Mtb has mechanisms to resist NO toxicity. Two genes were identified in Mtb, mpa (Mycobacterium proteasome ATPase) and pafA (proteasome associated factor), to be required for protection against NO. Importantly, mpa and pafA mutants are severely attenuated in mice. The proteasome is a multi-subunit, barrel shaped complex that degrades proteins. We hypothesize that Mpa and PafA chaperone proteins into the Mtb proteasome for degradation, but we do not know why this activity protects Mtb against NO or promotes virulence in mice. Thus, the goals of this proposal are to understand why proteasome activity protects Mtb against NO toxicity and promotes bacterial growth in vivo. We will examine proteasome-dependent gene expression to determine if genes regulated by the proteasome are required for NO-resistance or pathogenesis. In addition, we will determine how genes are regulated by the proteasome. Finally, we will identify substrates of the proteasome, which may reveal why protein degradation is critical for resistance to NO and survival in vivo. Relevance to public health: With increased age expectancy, prevalence of HIV infections and number of persons taking immunosuppressive drugs, the chances of contracting tuberculosis increases. Furthermore, tuberculosis therapy takes 6-9 months, a problem that leads to decreased compliance for taking antibiotics and increased chances of developing drug-resistant strains of Mtb. Taken together it will be important to develop faster acting drugs to new targets in Mtb in order to better treat tuberculosis in the future.

描述（由申请人提供）：每年全球约有200万人杀死约200万人。针对结核分枝杆菌（MTB）感染的关键防​​御是巨噬细胞生产一氧化氮（NO）。尽管没有对照MTB的生长，但它很少对宿主的细菌进行消毒。因此，MTB可能具有抵抗毒性的机制。在MTB，MPA（蛋白酶体ATPase）和PAFA（蛋白酶体相关因子）中鉴定了两个基因，以防止NO。重要的是，小鼠中MPA和PAFA突变体严重减弱。蛋白酶体是一种多纯料的桶形复合物，可降解蛋白质。我们假设MPA和PAFA伴侣蛋白进入MTB蛋白酶体降解，但我们不知道为什么这种活性可以保护MTB免受NO或促进小鼠的毒力。因此，该提案的目标是了解为什么蛋白酶体活动可以保护MTB免受无毒性，并促进体内细菌的生长。我们将检查蛋白酶体依赖性基因表达，以确定无抗性或发病机理所需的蛋白酶体调节的基因。此外，我们将确定基因如何受蛋白酶体的调节。最后，我们将确定蛋白酶体的底物，这可能揭示了为什么蛋白质降解对于对NO的耐药性和体内生存至关重要。与公共卫生有关：随着年龄的增长，艾滋病毒感染的流行和服用免疫抑制药物的人数，结核病的机会增加。此外，结核病疗法需要6-9个月，这一问题导致服用抗生素的依从性和增加抗药性MTB菌株的机会增加。综上所述，将更快的作用药物开发为MTB中的新靶标，以便在将来更好地治疗结核病。