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Principal Investigator: CARL Francis NATHAN
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2024
Award: $3,048,982
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <Aerosols><Air><Animal Model><Animal Models and Related Studies><Animals><Area><Basic Research><Basic Science><Biochemical><Biology><Biophysics><Burn injury><Burns><CO2><COVID-19><CV-19><Candidate Disease Gene><Candidate Gene><Carbon Dioxide><Carbonic Anhydride><Cause of Death><Cavia><Cessation of life><Characteristics><Communicable Diseases><Communities><Coronavirus Infectious Disease 2019><Coughing><Death><Development><Devices><Discipline><Disease><Disorder><Drug Targeting><Ensure><Environmental Factor><Environmental Risk Factor><Event><Foundations><Gases><Generations><Genes><Genetic><Genomics><Goals><Grips><Guinea Pigs><Guinea Pigs Mammals><H+ element><Host Factor><Host Factor Protein><Human><Human Resources><Humidity><Hydrogen Ions><Hydrogen Oxide><In Vitro><Incidence><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Integration Host Factors><Intervention><Intervention Strategies><Investigators><Knowledge><Life Cycle><Life Cycle Stages><Lipids><Liquid substance><Lung><Lung Respiratory System><Lung damage><M tb><M tuberculosis><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Manpower><Mechanics><Metabolic><Metabolic Pathway><Methods><Microbiology><Modeling><Modern Man><Modification><Molecular><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><O element><O2 element><Outcome><Oxygen><Pathogenicity Factors><Persons><Physics><Physiologic><Physiological><Physiology><Property><Protons><Research><Research Personnel><Researchers><Route><Sneezing><Source><Stress><TB infection><TB therapy><TB treatment><Technology><Temperature><Testing><Translating><Transmission><Travel><Tuberculosis><Virulence Factors><Water><aerosolized><biophysical foundation><biophysical principles><biophysical sciences><burned><chemotherapy><clinical phenotype><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><developmental><disseminated TB><disseminated tuberculosis><environmental risk><experiment><experimental research><experimental study><experiments><fluid><gene function><gene testing><gene-based testing><genetic testing><genome wide screen><grasp><guinea pig model><improved><infection due to Mycobacterium tuberculosis><innovate><innovation><innovative><interventional strategy><life course><lipidomics><liquid><lung injury><mechanic><mechanical><metabolism measurement><metabolomics><metabonomics><model of animal><mortality><mouse model><mtb><murine model><new approaches><new technology><novel><novel approaches><novel strategies><novel strategy><novel technologies><pandemic><pandemic disease><pathogen><personnel><pre-clinical><preclinical><pressure><programs><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><reproductive><respiratory><response><tool><transmission blocking><transmission process><treat M. tuberculosis><treat Mtb><treat Mycobacterium tuberculosis><treat tb><treat tuberculosis><tuberculosis infection><tuberculosis therapy><tuberculosis treatment><tuberculous spondyloarthropathy>