The Mycobacterium Tuberculosis Dormancy Program

描述(申请人提供)：世界上三分之一的人口感染结核分枝杆菌(MTB)，其中大多数感染处于潜伏状态。结核杆菌可以在肺部病变中保持不活跃，但几十年后才会作为新的结核病爆发而出现。目前对结核病的治疗通常需要在几个月内使用多种抗菌剂，这可能是因为结核病变中的杆菌以耐药、休眠的状态存在。了解细菌在潜伏感染阶段的生理学对于控制并最终根除结核病的目标至关重要。我们已经证明，当有氧呼吸受到阻碍时(由于氧气的还原或一氧化氮的存在)，杆菌强烈地诱导一个共同调节的48个基因的遗传程序，称为“休眠调节子”。这一调节基因编码了适应长期存活的“休眠”或非增殖状态所需的程序。芽孢杆菌在厌氧非繁殖状态下的生存需要能量守恒、维持氧化还原平衡的替代机制以及保护DNA和蛋白质的机制。我们的工作假设是：休眠调节子是一种遗传程序，它使结核杆菌在潜伏期存活。为了验证这一假设，我们将研究休眠MTB的关键方面，涉及休眠调节蛋白在休眠期间的核苷酸和核酸生物学中的作用。本文提出的研究对于了解结核杆菌如何在潜伏感染期间无限期存活至关重要，并表征了许多药物开发的候选靶点。这项研究赞扬了与俄罗斯分子诊断和治疗研究中心的合作。一份联合提案将提交给美国卫生与公众服务部生物技术参与计划，该计划将解决人类感染中休眠的结核分枝杆菌的各个方面。

DESCRIPTION (provided by applicant): A third of the world's population is infected with Mycobacterium tuberculosis (MTB) and most of these infections are in a latent state. Tubercle bacilli can remain inactive in lung lesions only to emerge decades later as new outbreaks of tuberculosis. Current therapy for tuberculosis often involves the administration of multiple antimicrobial agents over several months, probably because bacilli exist in a drug tolerant, dormant-like state in tubercle lesions. Understanding the physiology of bacilli during the latent infection phase is central to the goal of controlling and ultimately eradicating tuberculosis. We have demonstrated that as aerobic respiration is impeded (by reduced oxygen or by the presence of nitric oxide), bacilli strongly induce a co-regulated 48-gene genetic program called the "dormancy regulon". This regulon encodes a program required for adaptation to a long-term viable "dormant" or non-proliferating state. Bacillus survival during an anaerobic non-proliferating state requires conservation of energy, alternative mechanisms to maintain redox balance, and mechanisms to protect DNA and proteins. Our working hypothesis is: The dormancy regulon is a genetic program that confers survival to MTB during latency. To test this hypothesis we will investigate key aspects of dormant MTB that involve the role of dormancy regulon proteins in nucleotide and nucleic acid biology during dormancy. The research proposed herein is pivotal to understanding how the tubercle bacillus survives indefinitely during latent infection, and characterizes numerous candidate targets for drug development. This study compliments a collaboration with the Russian Research Center for Molecular Diagnostics and Therapy. A joint proposal will be submitted to the US Department of Health and Human Services Biotechnology Engagement Program that will address aspects of dormant MTB in human infection.