The Mycobacterium Tuberculosis Dormancy Program

描述（由申请人提供）：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。结核杆菌可以在肺病变中保持不活跃状态，几十年后才作为结核病的新爆发而出现。目前的结核病治疗通常需要在几个月的时间内使用多种抗菌药物，这可能是因为结核病灶内的杆菌处于耐药、休眠状态。了解潜伏感染阶段杆菌的生理机能是控制和最终根除结核病目标的核心。我们已经证明，当有氧呼吸受到阻碍时（由于氧气减少或一氧化氮的存在），杆菌强烈诱导一种共调控的48个基因遗传程序，称为“休眠调节”。这个规则编码了一个适应长期可行的“休眠”或不扩散状态所需的程序。芽孢杆菌在无氧非增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：休眠规则是一种遗传程序，使MTB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，包括休眠调节蛋白在休眠期间在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，并确定了许多药物开发的候选靶点。这项研究补充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和人类服务部生物技术参与计划，该计划将解决人类感染休眠MTB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.