Transmission Aerobiology of M. tuberculosis: Genes and Metabolic Pathways That Sustain Mtb Across an Evolutionary Bottleneck

摘要 除非COVID超越它，否则结核病很可能会继续保持其作为领导者的可怕记录 人类死亡的传染性原因。人类是唯一已知的自然宿主和传播者 病原体，结核分枝杆菌(Mtb)。这意味着人与人之间通过空中传播 对结核分枝杆菌作为一个物种的生存至关重要。尽管多方面努力降低结核病的传播性，但结核病的 生殖数Ro仍然是经常致命的传染病中最高的之一。产气 传播是结核分枝杆菌生命周期中的一个阶段，它肯定受到了强大的进化压力，但 我们对结核分枝杆菌传播生物学的了解非常缺乏。这个问题几乎是无法解决的 缺乏合适的技术和动物模型的基础科学研究。本计划项目拟在 通过带来协同效应，为潜在的新传播阻断干预措施奠定基础科学基础 将研究人员和学科结合在一起，共同发动全基因组的协同攻击 在传播相关条件下筛选结核分枝杆菌的代谢、脂组和生化特征 对这些条件作出反应，引入和改进动物模型，并以气溶胶物理学为指南 和工具。项目1将确定结核分枝杆菌在主要状态之间的转换中生存所需的基因 病原体在气溶胶传播的途中、期间和之后遇到。项目2将确定受保护的、 结核分枝杆菌因应传播相关压力而进化的基本代谢程序，例如 湿度和气体成分的变化。项目3建立在最近发现的引起咳嗽的类脂的基础上 由结核分枝杆菌生产，以表征一种更有效的咳嗽类脂作为毒力因子并开发一种模型 以咳嗽为基础的豚鼠传播。项目4描述了材料的物理和流变性 与结核病传播相关的呼吸液的性质，并使用该信息来控制机械 产生与生理相关的可呼吸的结核分枝杆菌气溶胶。核心A确保高效地流动 这些相互连接的单位之间的信息、人员和物资，而核心B开发了鼠标模型 使用项目4的气雾化装置和设置来模拟传输，并将该模型应用于 确认结核分枝杆菌依靠哪些基因在气溶胶传播给新宿主后存活下来。

ABSTRACT Unless COVID overtakes it, tuberculosis is likely to keep its grip on its grim record of being the leading infectious cause of human death. Humans are the only known natural host and transmitting reservoir for the causative agent, Mycobacterium tuberculosis (Mtb). This means that person-to-person transmission through air is essential for Mtb's survival as a species. Despite multifaceted efforts to reduce TB's transmissibility, TB's reproductive number, Ro, remains among the highest of frequently-lethal infectious diseases. Aerogenic transmission is a stage in Mtb's life cycle that must have been subjected to strong evolutionary pressures, yet our knowledge of Mtb's transmission biology is sorely lacking. The problem has been nearly inaccessible to basic-science study for want of suitable technologies and animal models. This Program Project proposes to lay a basic-science foundation for potential new transmission blocking interventions by bringing a synergistic combination of investigators and disciplines together for a collaborative attack that mobilizes genome-wide screening under transmission-relevant conditions, characterizes Mtb's metabolomic, lipidomic and biochemical responses to those conditions, introduces and improves animal models, and uses aerosol physics as a guide and tool. Project 1 will identify genes that Mtb requires to survive the transitions between major states that the pathogen encounters en route to, during and after aerosol transmission. Project 2 will identify conserved, essential metabolic programs in Mtb that have evolved in response to transmission-related stresses, such as changes in humidity and gas composition. Project 3 builds on the recent discovery of cough-inducing lipids produced by Mtb to characterize an even more potent tussive lipid as a virulence factor and to develop a model of cough-based transmission among guinea pigs. Project 4 characterizes the physical and rheological properties of respiratory fluids relevant to TB transmission and uses that information to control the mechanical generation of physiologically relevant, respirable aerosols of Mtb. Core A ensures the efficient flow of information, personnel and materiel among these interconnected units, while Core B develops a mouse model of simulated transmission using the aerosolization device and settings of Project 4 and applies that model to confirm which genes Mtb depends on to survive aerosol transmission to a new host.