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

> **NIH NIH P01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $3,258,815

## Abstract

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.

## Key facts

- **NIH application ID:** 10190646
- **Project number:** 1P01AI159402-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** CARL Francis NATHAN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $3,258,815
- **Award type:** 1
- **Project period:** 2021-05-13 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10190646

## Citation

> US National Institutes of Health, RePORTER application 10190646, Transmission Aerobiology of M. tuberculosis: Genes and Metabolic Pathways That Sustain Mtb Across an Evolutionary Bottleneck (1P01AI159402-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10190646. Licensed CC0.

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