A Multidisciplinary Approach to Understanding TB Latency and Reactivation

描述(由申请人提供)：全球根除结核病工作面临的一个主要挑战是，20亿人潜伏感染结核分枝杆菌，其中许多人，特别是在艾滋病毒合并感染的情况下，将发展为再激活疾病。由于缺乏适当的研究模型和分子工具，深入了解结核分枝杆菌在宿主中持续存在的分子机制的努力一直受到阻碍。目前的研究重点是确定特定模型中结核病潜伏期和重新激活所需的单个结核分枝杆菌基因或宿主因素，并推断它们与人类结核病潜伏期和重新激活的相关性。这一建议的中心假设是，没有单一的宿主或微生物途径负责结核分枝杆菌进入潜伏期或出现潜伏期，而是这些复杂的现象可归因于多个相互依赖的宿主和分枝杆菌分子网络，而不是从任何一个特定的模型推导出来的。使用系统生物学方法，包括几种新的潜伏结核感染动物模型，结合转录、蛋白质组、遗传、成像和计算技术，然后使用人类样本进行实验验证，我们将确定负责免疫控制结核分枝杆菌生长的宿主细胞因子网络，以及结核杆菌生长限制和重新激活所需的结核分枝杆菌调控和代谢途径。我们的数据有望产生：1)针对非复制型杆菌的新的潜在药物靶点，目标是缩短结核病化疗的持续时间；2)针对感染潜伏期和重新激活疾病的新的诊断标记；以及3)无法重新激活的新的减毒疫苗候选，这在艾滋病毒/艾滋病的背景下将特别重要。 公共卫生相关性：结核病的抗生素治疗需要至少6个月的治疗，因为导致结核病的细菌可能在受感染的宿主中“休眠”，变得非常难以用现有的药物杀死正在分裂的细菌。在这项提案中，我们计划使用多学科方法来揭示导致结核病细菌停止分裂并在免疫系统减弱时再次开始生长的一些重要机制。我们的结果有望产生新的药物靶点，以缩短治愈结核病所需的时间，以及新的候选疫苗和针对不同感染阶段的诊断测试。

DESCRIPTION (provided by applicant): A major challenge facing global tuberculosis (TB) eradication efforts is the fact that two billion people are latently infected with Mycobacterium tuberculosis (Mtb), many of whom, especially in the setting of HIV co-infection, will develop reactivation disease. Efforts to gain insight into the molecular mechanisms by which Mtb persists in the host have been impeded by the lack of adequate research models and molecular tools. Current research has focused on identifying individual Mtb genes or host factors required for TB latency and reactivation in specific models and inferring their relevance for TB latency and reactivation in humans. The central hypothesis of this proposal is that no single host or microbial pathway is responsible for Mtb entry into or emergence from latency, but rather, that these complex phenomena are attributable to multiple interdependent host and mycobacterial molecular networks, which cannot be deduced from any one particular model. Using a systems biology approach, including several novel animal models of latent TB infection in combination with transcriptional, proteomic, genetic, imaging, and computational techniques, followed by experimental verification of the data using human samples, we will identify host cytokine networks responsible for immunological control of Mtb growth, as well as Mtb regulatory and metabolic pathways required for bacillary growth restriction and reactivation. Our data are expected to yield: 1) Novel potential drug targets for nonreplicating bacilli, with the goal of shortening the duration of TB chemotherapy; 2) Novel diagnostic markers specific to the latent stage of infection and to reactivation disease; and 3) Novel attenuated vaccine candidates with an inability to reactivate, which would be particularly important in the setting of HIV/AIDS. PUBLIC HEALTH RELEVANCE: Antibiotic treatment for TB requires at least 6 months of therapy because the germs that cause TB can go "dormant" in the infected host, becoming very difficult to kill with currently available drugs, which kill dividing bacteria. In this proposal, we plan to use a multidisciplinary approach to uncover some of the important mechanisms that lead TB germs to stop dividing and to start growing again when the immune system weakens. Our results are expected to yield new drug targets to shorten the time it takes to cure TB, as well as new vaccine candidates and diagnostic tests for different stages of the infection.