# Study of M. tuberculosis under human host selection to identify virulence and barrier lipids (Project 1)

> **NIH NIH U19** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $260,407

## Abstract

Project 1. Study of M. tuberculosis under human host selection to identify virulence and barrier lipids
Project Leader: D. Branch Moody
Coinvestigators: Kyu Rhee, Jacob Mayfield
Collaborating Investigators: Adriaan Minnaard (Core C), Jeremy Rock (Core D), Clare Smith (Core E)
ABSTRACT
Comparative genomics has served as a dominant paradigm for tracking the tuberculosis (TB) epidemic,
understanding Mycobacterium tuberculosis (Mtb) virulence and developing new drugs and diagnostics.
Mycobacterial metabolism, in contrast, has been viewed as invariant feature of all clinical Mtb strains. Through
comparative metabolomic profiling of ~10,000 lipids among 84 patient-derived Mtb strains, we discovered that
Mtb’s pathognomonic lipid envelope shows identifiable patterns of variance among strains circulating among
human populations. To determine the impact of phenotypic diversity within the infecting bacterial population,
we will map cell wall lipid variation among 140 Mtb strains among TB patients from Masiphulemele, South
Africa. The resulting lipid map will describe variations in lipid composition among Mtb strains transmitting in
community. From a biological perspective, Mtb’s lipid envelope forms the primary interface with the host and is
therefore a direct and ongoing biochemical target of evolutionary selection. This project aims to reveal the
previously undescribed chemical diversity and lipid products that have arisen as a consequence of host- and
drug-derived clinical pressure. Using organism wide lipid profiling and genome wide sequencing, we have
identified 42 lipid-gene pairs that dominate in Mtb strain variance, as well as 1150 lipid species overexpressed
in virulent Mtb and 250 lipids selectively expressed at the host interface. Preliminary data support our ability to
then link these lipids to specific bacterial genes, even when prior to knowledge of the metabolite’s structure or
a gene’s function is lacking. CRISPR interference strategies will then establish causal linkages between genes
of unknown function and newly discovered lipids. We will further test lipid deficient strains in collaborative cross
mice to reveal specific roles of newly identified lipids in Mtb virulence. These discovery studies will identify
biologically important lipids that determine key outcomes in virulence, the host interface and Mtb survival in
vivo, supporting new approaches for tuberculosis diagnosis and treatment.

## Key facts

- **NIH application ID:** 10271484
- **Project number:** 1U19AI162584-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** DAVID Branch MOODY
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $260,407
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271484

## Citation

> US National Institutes of Health, RePORTER application 10271484, Study of M. tuberculosis under human host selection to identify virulence and barrier lipids (Project 1) (1U19AI162584-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10271484. Licensed CC0.

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