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: 10190650
• 负责人: Kyu Y Rhee
• 金额: $ 79.2万
• 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/10190650
• 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; 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; Rehydrations; Reporting; Saline; Series; Source; Stress; Testing; Tuberculosis; Vaccines; atmospheric carbon dioxide; carbonate dehydratase; clinically relevant; comparative; genetic approach; genome sequencing; lipidome; lipidomics; microbial; novel; pandemic disease; physiologic model; pressure; prevent; programs; response; transcriptome; transcriptomics; 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.

抽象的 结核病（TB）既是死亡的最可传染性原因之一，也是由于 全世界是一种传染病，使其成为由于可治愈疾病而导致的主要死亡原因。控制 因此，大流行不仅需要更快，更有效的诊断测试和治疗方法，而且还需要新颖 特定的传输阻塞干预措施。该项目侧重于后者，并试图确定保守的 结核分枝杆菌（MTB）中的特定代谢过程，TB的致病药物 抑制可能会损害其从一个宿主传播到另一个宿主的传播期间的生存。这个项目 特别是利用MTB在人类中的独家进化历史，既是宿主，也只有已知的水库， 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 对于物种生存至关重要的循环。尽管它的性质不稳定，看似异质 传输事件涉及许多过渡，例如气体组成和干燥的变化 压力本质上是相对不变且高度重复的压力。我们假设这些变化 已导致MTB中特定和自适应代谢反应的进化选择 可以预见的是，它可以完善其生命周期的基本但不稳定的阶段，抑制它可能 减慢或防止其扩散。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，并与该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以及临床相关性中生存的重要性 正如从流行病学定义的设置中回收的临床MTB分离株的报道，推断的水平 传播性。