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Role of FHL-mediated formate metabolism in Mycobacterium tuberculosis persistence

FHL介导的甲酸盐代谢在结核分枝杆菌持久性中的作用

基本信息

批准号：
8496708
负责人：
THOMAS C. ZAHRT
金额：
$ 17.4万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8496708
关键词：
Acid Fast Bacillae Staining Method Address Antibiotics Bacteria Biological Assay Biology Carbon Dioxide Cell Respiration Cessation of life Complement Complex Development Energy Metabolism Enterobacteriaceae Environment Enzymes Escherichia coli Formate dehydrogenase Formates Future Gases Gene Expression Genetic Granuloma Growth Human Hypoxia Immunosuppression In Vitro Individual Infection Knowledge Lead Link Lung diseases Maintenance Mediating Metabolism Morbidity - disease rate Multienzyme Complexes Mycobacterium tuberculosis Nitric Oxide Operon Oxidants Physiological Physiology Play Population Production Proteomics Respiration Role Shapes Signal Transduction Source Staging Testing Therapeutic Intervention Time Tuberculosis base formate hydrogenlyase in vivo insight latent infection mortality mutant novel oxidation pathogen research study response retinal rods success

项目摘要

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis is a rod-shaped, acid-fast, human-specific pathogen and is the causative agent of the respiratory disease tuberculosis (TB). The bacterium is a significant source of morbidity and mortality worldwide, and is currently predicted to infect approximately 2 billion individuals. The success of M. tuberculosis as a pathogen is closely linked with its ability to establish latent infections in susceptible individuas and reactivate at later timed during periods of immunosuppression. Determinants important for the establishment, maintenance, and reactivation of M. tuberculosis from long-term, persistent infection within the host are poorly understood. It is thought that latency initiates following encasement of M. tuberculosis within granulomatous lesions, and the recognition of specific signals present within this environment that inhibit aerobic respiration and promote the transition of M. tuberculosis into an altered physiological state of nonreplicating persistence (NRP). Recently, a locus (Rv0081-Rv0088) predicted to encode determinants comprising a formate hydrogenlyase (FHL) were found to be upregulated following exposure of M. tuberculosis to conditions (hypoxia and nitric oxide) promoting NRP in vitro. In addition, this locus was found to be directly regulated by two response regulators (DosR/DevR and MprA) known to contribute to persistence by M. tuberculosis in vitro and in vivo. FHL plays an important role in energy metabolism within enteric bacteria during periods of microaerophilic/anaerobic growth by mediating the oxidation of formate to CO2 and H2 in the absence of an external electron acceptor. This proposal seeks to fill a current gap in our knowledge by investigating aspects of M. tuberculosis metabolism under physiologically relevant conditions. We hypothesize that M. tuberculosis synthesizes a functional FHL enzyme complex that is required for energy metabolism and survival during periods of NRP. To address this hypothesis, two specific aims have been proposed. First, the ability of M. tuberculosis FHL to mediate the oxidation of formate to CO2 and H2 will be examined using spectrophotometric- and gas chromatographic-based approaches. Second, determinants comprising the predicted FHL will be examined to determine if they interact to form FHL and are required for survival of M. tuberculosis during NRP. Collectively, these studies are expected to provide novel insights into M. tuberculosis physiology under conditions associated with NRP and latency. Delineation of the basis for formate metabolism may also identify new enzymes that can be targeted for therapeutic intervention of M. tuberculosis during periods of NRP when the bacterium is otherwise recalcitrant to currently available antibiotics.

描述（由申请方提供）：结核分枝杆菌是一种杆状、耐酸、人类特异性病原体，是呼吸道疾病结核病（TB）的病原体。该细菌是世界范围内发病率和死亡率的重要来源，目前预计将感染约20亿人。M的成功。结核病作为一种病原体与其在易感个体中建立潜伏感染并在免疫抑制期间稍后时间重新激活的能力密切相关。对M.结核病在宿主体内的长期、持续感染的机制尚不清楚。据认为，潜伏期在M.肉芽肿病变内的结核，以及识别这种环境中存在的抑制有氧呼吸和促进转化的特定信号分枝结核病转化为非复制持久性（NRP）的改变的生理状态。最近，预测编码甲酸氢解酶（FHL）决定簇的基因座（Rv 0081-Rv 0088）被发现在暴露于M.结核病的条件（缺氧和一氧化氮）促进NRP在体外。此外，该位点被发现是直接调节的两个响应调节器（DosR/DevR和MprA）已知有助于持久性由M。结核病在体外和体内。FHL在微需氧/厌氧生长期间通过在没有外部电子受体的情况下介导甲酸盐氧化为CO2和H2在肠道细菌内的能量代谢中起重要作用。本文试图通过对M.结核代谢在生理相关条件下。我们假设M.肺结核合成一种功能性FHL酶复合物，该酶复合物是NRP期间能量代谢和存活所需的。为了解决这一假设，提出了两个具体目标。第一，M.结核FHL介导的甲酸氧化为CO2和H2将使用分光光度法和气相色谱法为基础的方法进行检查。其次，将检查构成预测FHL的决定因素，以确定它们是否相互作用形成FHL，以及是否是M存活所必需的。NRP期间的肺结核。总的来说，这些研究有望为M.结核生理学与NRP和潜伏期相关的条件下。对甲酸代谢基础的描述也可以鉴定出新的酶，这些酶可以作为M.在NRP期间，当细菌对目前可用的抗生素不敏感时，可以治疗结核病。