A Multidisciplinary Approach to Understanding TB Latency and Reactivation

了解结核病潜伏期和再激活的多学科方法

• 批准号: 8145243
• 负责人: Joel S. Bader
• 金额: $ 78.83万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-17 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145243
• 关键词: AIDS/HIV problem; Animal Model; Antibiotic Therapy; Antibiotics; Attenuated Vaccines; Bacillus (bacterium); Bacteria; Biological Assay; Biological Markers; Cavia; Complex; Computational Technique; Computer Simulation; Cytokine Network Pathway; Data; Defect; Development; Diagnostic tests; Disease; Drug Delivery Systems; Equilibrium; Excision; Gene Combinations; Gene Expression; Genes; Genetic Techniques; Germ; Goals; Growth; HIV; Human; Hypoxia; Image; Imaging Techniques; Immune; Immune system; Individual; Infection; Integration Host Factors; Knock-out; Lead; Lesion; Lung; Metabolic Pathway; Metabolism; Modeling; Molecular; Molecular Models; Mus; Mycobacterium tuberculosis; Oryctolagus cuniculus; PET/CT scan; Pathology; Pathway interactions; Patients; Peptide Fragments; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Plasma; Proteins; Proteomics; Regulatory Pathway; Research; Reverse Transcriptase Polymerase Chain Reaction; Sampling; Signal Transduction; Staging; Systems Biology; Testing; Time; Tuberculosis; animal tissue; base; chemotherapy; cohort; cytokine; in vitro Model; in vivo; insight; interdisciplinary approach; killings; laser capture microdissection; latent infection; microbial; molecular modeling; mutant; mycobacterial; nonhuman primate; novel; novel diagnostics; novel vaccines; public health relevance; reactivation from latency; response; tool; vaccine candidate

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.

描述（由申请人提供）：全球结核病（TB）根除工作面临的一个主要挑战是，有20亿人潜伏性感染了结核杆菌（Mtb），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。由于缺乏足够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受到阻碍。目前的研究集中在确定特定模型中结核潜伏期和再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潜伏期和再激活的相关性。该提议的中心假设是，没有单一的宿主或微生物途径负责Mtb进入潜伏期或从潜伏期出现，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，这不能从任何一个特定的模型推导出来。使用系统生物学方法，包括几种新型的潜伏性TB感染的动物模型，结合转录，蛋白质组学，遗传学，成像和计算技术，然后使用人类样本的数据进行实验验证，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，以及结核分枝杆菌的调节和代谢途径所需的细菌生长限制和重新激活。我们的数据预计将产生：1）新的潜在药物靶点的非复制杆菌，目标是缩短结核化疗的持续时间; 2）新的诊断标志物特异性的潜伏期感染和再激活疾病;和3）新的减毒疫苗候选人，无法再激活，这将是特别重要的艾滋病毒/艾滋病的设置。 公共卫生关系：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以在感染的宿主中“休眠”，变得非常难以用目前可用的药物杀死，这些药物杀死分裂的细菌。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菌停止分裂并在免疫系统减弱时重新开始生长的一些重要机制。我们的研究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，以及针对感染不同阶段的新候选疫苗和诊断测试。