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

• 批准号: 10682926
• 负责人: CARL Francis NATHAN
• 金额: $ 23.6万
• 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/10682926
• 关键词: Aerosols; Air; Animal Model; Animals; Area; Basic Science; Biochemical; Biology; Biophysics; Burn injury; Candidate Disease Gene; Carbon Dioxide; Cause of Death; Cavia; Cessation of life; Characteristics; Communicable Diseases; Communities; Coughing; Development; Devices; Discipline; Disease; Drug Targeting; Ensure; Environmental Risk Factor; Event; Foundations; Gases; Generations; Genes; Genetic; Genomics; Goals; Human; Human Resources; Humidity; In Vitro; Incidence; Infection; Integration Host Factors; Intervention; Knowledge; Life Cycle Stages; Lipids; Liquid substance; Lung; Mechanics; Metabolic; Metabolic Pathway; Methods; Microbiology; Modeling; Modification; Molecular; Mycobacterium tuberculosis; Outcome; Oxygen; Persons; Physics; Physiological; Physiology; Problem Solving; Property; Protons; Research; Research Personnel; Route; Sneezing; Source; Stress; Technology; Temperature; Testing; Time; Translating; Travel; Tuberculosis; Ursidae Family; Virulence Factors; Water; aerosolized; base; chemotherapy; clinical phenotype; coronavirus disease; experimental study; gene function; genetic testing; genome wide screen; grasp; guinea pig model; improved; innovation; lipidomics; lung injury; metabolomics; mortality; mouse model; new technology; novel; novel strategies; pandemic disease; pathogen; pre-clinical; pressure; programs; reproductive; respiratory; response; tool; transmission process; tuberculosis treatment

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Covid超过它，否则结核病可能会保持其严峻的领先记录 人类死亡的传染性原因。人类是唯一已知的自然寄主，也是传输储层 病因，结核分枝杆菌（MTB）。这意味着通过空中传播人对人的传播 对于MTB作为一种物种的生存至关重要。尽管为了降低结核病的可传播性而做出了多方面的努力，但TB的努力 生殖数量RO，仍然是经常致命的传染病中最高的。充气 传播是MTB生命周期的一个阶段，必须承受强大的进化压力，但是 我们对MTB传播生物学的了解非常缺乏。这个问题几乎无法解决 基础科学研究，缺乏合适的技术和动物模型。该计划项目建议 通过带来协同作用，是潜在的新传输阻断干预措施的基本科学基础 研究人员和学科的结合在一起，进行协作攻击，动员全基因组 MTB代谢组，脂质组和生化的特征是在传播相关条件下进行筛查 对这些条件的反应，引入和改善动物模型，并使用气溶胶物理作为指导 和工具。项目1将确定MTB所需的基因，以在主要国家之间的过渡中生存 病原体在通往气溶胶传播的途中，期间和之后遇到。项目2将确定保守的 MTB的基本代谢程序是根据传播相关应力而发展的，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脂质的基础上 由MTB生产的，以表征更有效的刺激性脂质为毒力因子，并开发模型 豚鼠中基于咳嗽的传播。项目4表征了身体和流变学 与结核病传输相关的呼吸道流体的特性，并使用该信息来控制机械 MTB的生理相关，可呼吸的气溶胶产生。核心A确保有效流动 这些相互联系的单元中的信息，人员和物资，而核心B开发了鼠标模型 使用雾化设备和项目4的设置进行模拟传输，并将该模型应用于 确认哪些基因MTB取决于将气溶胶传播生存到新宿主。