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

基本信息

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
项目类别：
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

项目摘要

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）：全球根除结核病 (TB) 工作面临的一个主要挑战是，有 20 亿人潜伏感染结核分枝杆菌 (Mtb)，其中许多人，特别是在同时感染艾滋病毒的情况下，将发展再激活疾病。由于缺乏足够的研究模型和分子工具，深入了解 Mtb 在宿主体内持续存在的分子机制的努力受到阻碍。目前的研究重点是确定特定模型中结核病潜伏期和再激活所需的单个结核分枝杆菌基因或宿主因子，并推断它们与人类结核病潜伏期和再激活的相关性。这一提议的中心假设是，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，而这不能从任何一个网络中推断出来特定型号。使用系统生物学方法，包括几种新型潜伏性结核感染动物模型，结合转录、蛋白质组、遗传、成像和计算技术，然后使用人类样本对数据进行实验验证，我们将确定负责免疫学的宿主细胞因子网络控制 Mtb 生长，以及限制和重新激活细菌生长所需的 Mtb 调节和代谢途径。我们的数据预计将产生：1）针对非复制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）针对感染潜伏期和再激活疾病的新型诊断标记物； 3) 无法重新激活的新型减毒候选疫苗，这在艾滋病毒/艾滋病的情况下尤其重要。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以在受感染的宿主体内“休眠”，很难用目前可用的杀死分裂细菌的药物杀死。在这项提案中，我们计划采用多学科方法来揭示一些导致结核病菌在免疫系统减弱时停止分裂并重新开始生长的重要机制。我们的研究结果预计将产生新的药物靶点，以缩短治愈结核病的时间，以及新的候选疫苗和针对感染不同阶段的诊断测试。