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: 10190646
• 负责人: CARL Francis NATHAN
• 金额: $ 325.88万
• 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/10190646
• 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; improved; innovation; lipidomics; lung injury; metabolomics; mortality; mouse model; new technology; novel; novel strategies; pandemic disease; pathogen; porcine model; 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.

摘要