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.

抽象的 结核病 (TB) 既是最具传染性的死亡原因之一，也是导致死亡的主要原因之一 一种世界范围内的传染病，使其成为可治愈疾病导致死亡的主要原因。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，还需要新颖和 具体的传播阻断干预措施。该项目重点关注后者，并寻求识别保守的 结核分枝杆菌 (Mtb) 的特定代谢过程，结核病的病原体，其 抑制有可能损害其从一个宿主传播到下一个宿主期间的生存。这个项目 特别利用 Mtb 在人类中作为宿主和唯一已知宿主的独特进化历史， 这使得传播不仅是其致病性的基本特征，而且是其生命的固有阶段 作为一个物种的生存至关重要的循环。尽管其性质不稳定且看似异质，但所有 传输事件涉及许多转变，例如气体成分的变化和干燥 压力，本质上是相对不变且高度重复的。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 使其能够以可预测的方式完成其生命周期中这一重要但不稳定的阶段，对其进行抑制可能会 减缓或阻止其传播。该项目建立在初步数据的基础上，这些数据已确定了几个此类 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重要性以及临床相关性 据报告，从流行病学定义的环境中回收的临床结核分枝杆菌分离株和推断的结核分枝杆菌水平 传播性。