Hypoxia, Latency and Reactivation in M.tuberculosis

描述（由申请人提供）：致病成功的核心 结核分枝杆菌（MTB）是其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。 大约三分之一的世界人口窝藏潜在的MTB， 使结核病控制工作复杂化。潜伏性肺结核患者 在一生中有10%的机会患上活动性疾病， 这样的人感染艾滋病毒，复发结核病的风险就会增加 每年增长8 - 10%。人类宿主体内的低血糖症广泛存在于 被认为对潜伏性结核病的发展至关重要，但MTB 对缺氧的适应性反应目前知之甚少。的目标 这个建议是定义结核分枝杆菌缺氧反应，因为它与潜伏期有关 和重新激活。我们将机械地剖析这种反应，并分析 低氧在潜伏性结核病和再激活中的作用。这项建议会 定义其对氧张力降低的反应包括MTB的基因 缺氧调节子我们还将关注MTB α-晶体蛋白（Acr）， 微需氧菌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-晶体蛋白调节 确定氧气张力控制的精确机制的机器 MTB基因表达。其结果将是更好的工具来应对威胁， 超过10亿人患有潜伏性结核病，其中数百万人 现在或即将同时感染人类免疫缺陷病毒，艾滋病病毒。

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.