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

摘要 除非新冠疫情超过它，否则结核病可能会继续保持其作为主要疾病的严峻记录。 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宿主， 病原体，结核分枝杆菌（Mtb）。这意味着人与人之间的空气传播 对结核杆菌的生存至关重要尽管为降低结核病的传播性做出了多方面的努力， 生殖数Ro仍然是最高的经常致命的传染病之一。产气 传播是结核分枝杆菌生命周期中的一个阶段，必须受到强大的进化压力，但 我们对结核病传播生物学的了解非常缺乏。这个问题几乎是无法解决的， 基础科学研究缺乏合适的技术和动物模型。该项目计划将 为潜在的新的传播阻断干预措施奠定基础科学基础， 研究人员和学科的结合，共同进行协作攻击，动员全基因组 在传播相关条件下筛选，表征Mtb的代谢组学、脂质组学和生物化学 这些条件的反应，介绍和改进动物模型，并使用气溶胶物理学作为指导 和工具。项目1将确定结核分枝杆菌需要在主要状态之间的过渡中生存的基因， 病原体在气溶胶传播途中、期间和之后遭遇。项目2将确定保存， 结核分枝杆菌中的基本代谢程序，这些程序是为了应对传播相关的压力而进化的，例如 湿度和气体成分的变化。项目3建立在最近发现的咳嗽诱导脂质的基础上 由结核分枝杆菌产生，以表征作为毒力因子的更有效的咳嗽脂质，并开发模型 在豚鼠中的咳嗽传播。项目4描述了物理和流变特性 与结核病传播相关的呼吸流体的性质，并使用该信息来控制机械 产生Mtb的生理相关的可吸入气溶胶。核心A确保了 核心B开发一个鼠标模型， 使用雾化装置和项目4的设置模拟传播，并将该模型应用于 确认Mtb依赖哪些基因在气溶胶传播到新宿主中存活。

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.