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

结核分枝杆菌的传播空气生物学：跨越进化瓶颈维持结核分枝杆菌的基因和代谢途径

基本信息

批准号：
10610915
负责人：
CARL Francis NATHAN
金额：
$ 307.61万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
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

项目摘要

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.

抽象的除非新冠疫情取代结核病，否则结核病很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。人类是该病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通过空气传播对于 Mtb 作为一个物种的生存至关重要。尽管采取了多方面的努力来减少结核病的传播，但结核病的传染数 Ro 仍然是致死率最高的传染病之一。产气传输是山地车生命周期中的一个阶段，必定受到了强大的进化压力，但是我们对结核分枝杆菌传播生物学的了解非常缺乏。这个问题几乎无法解决缺乏合适技术和动物模型的基础科学研究。本计划项目拟铺设通过带来协同效应，为潜在的新传播阻断干预措施奠定基础科学基础研究人员和学科联合起来进行协同攻击，动员全基因组在传播相关条件下进行筛查，表征结核分枝杆菌的代谢组学、脂质组学和生化特征对这些条件的反应，引入和改进动物模型，并使用气溶胶物理学作为指导和工具。项目 1 将确定 Mtb 在主要状态之间的转换中生存所需的基因。气溶胶传播途中、期间和之后遇到病原体。项目 2 将识别保守的、结核分枝杆菌的重要代谢程序是为了响应与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 以最近发现的引起咳嗽的脂质为基础由 Mtb 生产，用于表征作为毒力因子的更有效的咳嗽脂质并开发模型豚鼠之间基于咳嗽的传播。项目 4 描述了物理和流变特性与结核病传播相关的呼吸液体的特性，并使用该信息来控制机械产生生理相关的、可吸入的结核分枝杆菌气溶胶。核心A确保高效流动这些相互关联的单元之间的信息、人员和物资，而 Core B 开发了小鼠模型使用项目 4 的气雾化装置和设置进行模拟传播，并将该模型应用于确认 Mtb 依靠哪些基因才能通过气溶胶传播到新宿主。