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: 8319411
• 负责人: Joel S. Bader
• 金额: $ 76.99万
• 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/8319411
• 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）消除工作面临的重大挑战是，有20亿人被严格感染结核分枝杆菌（MTB），其中许多人（尤其是在HIV共同感染的情况下）会出现重新激活疾病。缺乏足够的研究模型和分子工具阻碍了宿主中MTB持续存在的分子机制的努力。当前的研究重点是识别特定模型中TB潜伏期和重新激活所需的单个MTB基因或宿主因素，并推断其与人类中TB潜伏期和重新激活的相关性。该提议的中心假设是，没有任何单个宿主或微生物途径负责MTB进入或从潜伏期中进入或出现，而是这些复杂的现象归因于多个相互依存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中分配。使用系统生物学方法，包括几种新型潜在TB感染的动物模型，并结合转录，蛋白质组学，遗传，成像和计算技术，然后使用人类样品对数据进行实验验证，我们将确定宿主细胞因子网络，负责MTB的免疫控制MTB调节性和MTB调节性途径的免疫学控制，以及对MTB调节性的限制。我们的数据预计将产生：1）非复制杆菌的新型药物靶标，目的是缩短TB化学疗法的持续时间； 2）针对潜在感染和重新激活疾病的新型诊断标记； 3）新的减弱疫苗候选物，无法重新激活，这在艾滋病毒/艾滋病的情况下尤为重要。 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，因为引起结核病的细菌可能会在受感染宿主中“休眠”，因此很难用目前可用的药物杀死，这会杀死分裂细菌。在此提案中，我们计划使用多学科方法来揭示一些重要的机制，这些机制导致结核病细菌停止分裂并在免疫系统削弱时再次开始生长。我们的结果预计将产生新的药物靶标，以缩短治疗结核病的时间，以及新的疫苗候选物和诊断测试的不同感染阶段。