Project 2: Essential metabolic objectives of M. tuberculosis aerobiology

项目2：结核分枝杆菌有氧生物学的基本代谢目标

• 批准号: 10610922
• 负责人: Kyu Y Rhee
• 金额: $ 40.52万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-13 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610922
• 关键词: Aerosols; Air; Alleles; Anabolism; Animal Model; Antimicrobial Resistance; Area; Arginine; Atmosphere; Attention; Biological Assay; Buffers; CRISPR interference; Carbamyl Phosphate; Carbon Dioxide; Cause of Death; Clinic; Clinical; Collaborations; Communicable Diseases; Complex; Culture Media; Data; Desiccation; Diagnostic tests; Disease; Ensure; Environment; Enzymes; Epidemiology; Event; Face; Gases; Genes; Goals; Human; Hydration status; Hypoxia; Immunity; Impairment; In Vitro; Infection; Interruption; Intervention; Life; Life Cycle Stages; Lipids; Liquid substance; Location; Measurable; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modality; Modeling; Mus; Mycobacterium tuberculosis; Nature; Nucleotide Biosynthesis; Oryctolagus cuniculus; Pathogenicity; Phase; Phenotype; Physiological; Physiology; Purines; Pyrimidine; Recording of previous events; Reporting; Saline; Series; Source; Stress; Testing; Tuberculosis; Vaccines; aerosolized; atmospheric carbon dioxide; carbonate dehydratase; clinically relevant; comparative; genetic approach; genome sequencing; lipidome; lipidomics; microbial products; novel; pandemic disease; pandemic response; physiologic model; pressure; prevent; programs; response; transcriptome; transcriptomics; transmission blocking; transmission process; whole genome

ABSTRACT Tuberculosis (TB) is both among the most transmissible causes of death and the leading cause of death due to an infectious disease worldwide, making it the leading cause of death due to a curable disease. Control of the pandemic thus requires not only faster and more effective diagnostic tests and cures, but also novel and specific transmission blocking interventions. This project focuses on the latter, and seeks to identify conserved and specific metabolic processes in Mycobacterium tuberculosis (Mtb), the causative agent of TB, whose inhibition has the potential to impair its survival during transmission from one host to the next. This project specifically leverages Mtb's exclusive evolutionary history in humans as both host and only known reservoir, which has made transmission not only an essential feature of its pathogenicity but intrinsic phase of its life cycle that is essential for its survival as a species. Despite its erratic and seemingly heterogeneous nature, all transmission events involve a number of transitions, such as changes in gas composition and desiccation stress, that are comparatively invariant and highly repetitive in nature. We hypothesize that these changes have resulted in the evolutionary selection of specific and adaptive metabolic responses in Mtb that have equipped it to predictably complete this essential but erratic phase of its life cycle, inhibition of which might slow or prevent its spread. This project builds on preliminary data which have identified several such responses and, in collaboration with other Projects and Cores in this Program Project, will now test their essentiality for survival in a series of in vitro and animal models of aerosol transmission, and clinical relevance as reported by clinical Mtb isolates recovered from epidemiologically defined settings and inferred levels of transmissibility.

摘要 结核病（TB）是最易传播的死亡原因之一，也是由于结核病而导致死亡的主要原因。 这是一种世界范围内的传染病，是可治愈疾病导致死亡的主要原因。控制 因此，大流行病不仅需要更快和更有效的诊断测试和治疗， 具体的传输阻断干预措施。本项目的重点是后者，并寻求确定保守的 和结核分枝杆菌（Mtb）的特定代谢过程，结核病的病原体， 在从一个宿主到下一个宿主的传播过程中，抑制有可能损害其存活。这个项目 特别是利用结核分枝杆菌在人类中作为宿主和唯一已知的储存库的独特进化历史， 这使得传播不仅是其致病性的基本特征，而且是其生命的内在阶段 这是它作为一个物种生存所必需的。尽管其不稳定和看似异质性，所有 传输事件涉及许多转变，例如气体成分的变化和干燥 应力，这些应力在性质上相对不变且高度重复。我们假设这些变化 导致了结核分枝杆菌特异性和适应性代谢反应的进化选择， 装备它，以可预见地完成其生命周期的这一重要但不稳定的阶段，抑制它可能 减缓或防止其扩散。该项目建立在初步数据的基础上，这些数据已经确定了几个这样的 响应，并与本计划项目中的其他项目和核心合作，现在将测试他们的 在一系列气溶胶传播的体外和动物模型中生存的必要性和临床相关性 根据从流行病学定义的环境中回收的临床Mtb分离株报告， 可传递性