Hypoxia, Latency and Reactivation in M.tuberculosis

描述(由申请人提供)：致病成功的关键 结核分枝杆菌(MTB)是指它在人体内持续存在的能力 长期处于潜伏状态，不会引起任何明显的疾病症状。 世界上大约三分之一的人口患有潜伏的肺结核， 使结核病控制工作复杂化。潜伏性肺结核患者 一生中有大约10%的机会患上活动性疾病，当 这样的人感染艾滋病毒，患再激活结核病的风险增加 到每年8%-10%。人类宿主内的低氧条件广泛存在 被认为对潜伏结核病的发展至关重要，但结核分枝杆菌 对低氧的适应性反应目前还知之甚少。的目标是 该建议是定义与潜伏期有关的MTB缺氧性反应 和重新激活。我们将机械地剖析这种反应，并分析 低氧在潜伏性肺结核和复活中的作用。这项提议将 定义对氧分压降低的反应包括MTB的基因 低氧调节子。我们还将重点介绍MTBα-晶体蛋白(ACR)，这是一种成分 由微嗜氧性强烈诱导的低氧反应 条件。我们将确定表达的具体条件 α-晶状体蛋白及其调节剂是实现潜伏期或 重新激活。最后，我们将剖析α-晶体蛋白的调控。 用于确定氧分压控制的精密机构的机械 结核分枝杆菌基因的表达。其结果将是更好的工具来应对 超过10亿人患有潜在结核病，其中数百万人是 现在或不久将同时感染人类免疫缺陷病毒HIV。

DESCRIPTION (Provided by the applicant): Central to the pathogenic success of Mycobacterium tuberculosis (MTB) is its ability to persist within humans for long periods in a latent state, without causing any overt disease symptoms. Roughly one-third of the world population harbors latent MTB, greatly complicating efforts at tuberculosis control. A person with latent tuberculosis has about a 10 percent lifetime chance of developing active disease, and when such a person contracts HIV, the risk of developing reactivation TB increases to 8 - 10 percent per year. Hypoxic conditions within the human host are widely regarded as crucial for development of latent tuberculosis, but the MTB adaptive response to hypoxia is at present very poorly understood. The goal of this proposal is to define the MTB hypoxic response as it relates to latency and reactivation. We will mechanistically dissect this response and analyze the role of hypoxia in latent tuberculosis and reactivation. This proposal will define the genes whose response to reduced oxygen tension comprises the MTB hypoxia regulon. We will also focus on MTB alpha-crystallin (Acr), a component of the hypoxic response that is powerfully induced by microaerophilic conditions. We will determine the specific conditions in which expression of alpha-crystallin and its regulators is necessary for achieving latency or reactivation. Finally, we will dissect the alpha-crystallin regulatory machinery to determine the precise mechanisms by which oxygen tension controls MTB gene expression. The result will be better tools to confront the threat to more than one billion persons with latent tuberculosis, millions of whom are now or will soon be co-infected the the human immunodeficiency virus, HIV.