Project 2: Essential metabolic objectives of M. tuberculosis aerobiology

摘要 结核病(TB)既是最易传播的死亡原因之一，也是由以下原因引起的主要死亡原因 一种世界性的传染病，使其成为一种可治愈的疾病导致的主要死亡原因。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，而且还需要新的和 具体的传播阻断干预措施。本项目侧重于后者，并试图确定保守的 以及结核分枝杆菌(Mtb)的特定代谢过程，结核分枝杆菌是结核病的病原体，其 在从一个宿主传播到下一个宿主的过程中，抑制有可能损害其生存。这个项目 特别利用结核分枝杆菌作为宿主和唯一已知的宿主在人类中的独特进化史， 这不仅使传播成为其致病性的基本特征，也使其成为其生命的内在阶段 对其作为一个物种的生存至关重要的循环。尽管它的性质不稳定和看似不同，但所有的 传输事件涉及许多转变，例如气体组成和干燥的变化 重音，在本质上是相对不变和高度重复的。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 装备它以可预见地完成其生命周期的这一基本但不稳定的阶段，抑制这一阶段可能 减缓或防止其传播。这个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，并与此计划项目中的其他项目和核心合作，现在将测试其 气雾剂传播的一系列体外和动物模型中生存的重要性和临床相关性 据临床报告，从流行病学定义的环境中发现的结核分枝杆菌分离株和推断的水平 传播性。

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.