Type II-NDHs in M. tuberculosis respiration and persistence

结核分枝杆菌呼吸和持久性中的 II-NDH 型

• 批准号: 8891858
• 负责人: THOMAS C. ZAHRT
• 金额: $ 19.13万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891858
• 关键词: Acid Fast Bacillae Staining Method; Address; Aerobic; Aerosols; Amino Acids; Bacillus (bacterium); Bacteria; Binding; Biochemical; Bioinformatics; Biological Models; Cell Respiration; Characteristics; Chimera organism; Complement; Consensus; Cytochrome c Reductase; Data; Deposition; Disease; Dose; Drug resistance; Electron Transport; Enzymes; Exhibits; Family member; Future; Generations; Granuloma; Human; Immune response; Immunosuppression; In Vitro; Individual; Infection; Intervention; Investigation; Lung; Lung diseases; Mediating; Modeling; Molecular Genetics; Morbidity - disease rate; Mycobacterium tuberculosis; NADH; Nitric Oxide; Organism; Oxidants; Oxygen; Oxygen measurement, partial pressure, arterial; Physiological; Physiology; Play; Population; Production; Quinones; Respiration; Respiratory Chain; Resuscitation; Role; Site; Specificity; Testing; Therapeutic Intervention; Tuberculosis; Vaccines; Variant; Virulence; antimicrobial; base; burden of illness; in vitro activity; in vivo; in vivo Model; insight; latent infection; member; mortality; mutant; new therapeutic target; novel; oxidation; pathogen; public health relevance; reactivation from latency; tuberculosis granuloma

 DESCRIPTION (provided by applicant): Mycobacterium tuberculosis is an acid-fast, human-specific pathogen and is the etiological agent of the respiratory disease tuberculosis (TB). Approximately 2 billion individuals are currently predicted to be latently infected with the tuberce bacillus. During latency, M. tuberculosis exists within host-generated granulomatous lesions in a poorly understood physiological state termed non-replicating persistence (NRP). It is generally thought that specific conditions initially encountered within granulomatous lesions, including oxygen-limitation and nitric oxide, inhibit aerobic respiration and induce the transition of M. tuberculosis into NRP for long-term survival during anaerobic dormancy. Aerobic and anaerobic respiration in M. tuberculosis is mediated in part by NADH dehydrogenases (NDH), enzymes which catalyze the oxidation of NADH to NAD+ with concomitant transfer of electrons to respiratory chain components. M. tuberculosis encodes one type-1 NDH and two type-2 NDHs. Recently, we identified a third predicted type-2 NDH (Rv1812c) that is regulated by determinants/conditions associated with M. tuberculosis persistence. Preliminary investigations described in this application indicate that Rv1812c encodes a type-2 NDH and participates in the resuscitation of M. tuberculosis from anaerobic dormancy. In addition, we provide bioinformatic evidence indicating that Rv1812c possesses unique structural, functional, and expression characteristics that distinguish it from the other two established type-2 NDHs (Ndh and NdhA) produced in M. tuberculosis. The two specific aims proposed in this application will allow us to investigate and compare the activities of the three type-2 NDHs produced in M. tuberculosis, and determine whether Rv1812c is required for M. tuberculosis NRP or its resuscitation from latency in vivo.

 描述（由申请方提供）：结核分枝杆菌是一种抗酸的人类特异性病原体，是呼吸道疾病结核病（TB）的病原体。目前预计约有20亿人潜伏感染结核杆菌。在潜伏期，M.结核病存在于宿主产生的肉芽肿性病变中，其生理状态知之甚少，称为非复制持续性（NRP）。一般认为，肉芽肿病变最初遇到的特定条件，包括氧限制和一氧化氮，抑制有氧呼吸并诱导M。结核病转化为NRP，以便在厌氧休眠期间长期存活。好氧呼吸和无氧呼吸在M.结核病部分地由NADH脱氢酶（NDH）介导，所述酶催化NADH氧化成NAD+，伴随着电子转移到呼吸链组分。M.结核病编码一种1型NDH和两种2型NDH。最近，我们发现了第三种预测的2型NDH（Rv 1812 c），其受与M相关的决定因素/条件的调节。结核病持续存在本申请中描述的初步研究表明Rv 1812 c编码2型NDH并参与M.厌氧休眠引起的肺结核此外，我们提供的生物信息学证据表明，Rv 1812 c具有独特的结构，功能和表达特征，将其与M中产生的其他两种已建立的2型NDH（Ndh和NdhA）区分开来。结核本申请中提出的两个具体目标将使我们能够调查和比较M中产生的三种2型NDH的活性。结核病，并确定是否Rv 1812 c所需的M.结核NRP或从体内潜伏期复苏。