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Dissecting virulence gene regulatory pathways in M. tuberculosis clinical isolates

Award Number: F32AI174653
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Dissecting virulence gene regulatory pathways in M. tuberculosis clinical isolates - Project Summary Infecting an estimated one quarter of the world’s population, M. tuberculosis (Mtb) is an ongoing threat to human health worldwide. Mtb infection can lead to a wide range of outcomes ranging from an asymptomatic latent infection to severe disease. These disease states are the function of bacterial, host, and environmental factors. Despite ongoing selection to adapt to the host environment, the contribution of Mtb’s genetic variation is an underappreciated variable in this equation. Evolution acts on regulation of gene expression to create large phenotypic diversity from small genetic change. Our long-term objective is to understand how evolution in Mtb’s regulatory network contributes to variation in disease outcome. In a preliminary study, we used a high-throughput transcriptomic pipeline we built to capture transcriptomes from 284 clinical isolates from Vietnam and Peru; we identified ~10% of well-transcribed genes were highly variable across isolates and linked expression outliers to mutations in transcriptional regulators or nearby regulatory regions. Unexpectedly, we identified an up to 17-fold range in expression of ESX-1 secreted effector proteins; a key virulence pathway, ESX-1 is required for productive infection. Based on these results, we propose two aims for this study. In Aim 1, since transcriptional regulation responds to the environment, we will capture transcriptomes from our isolate library during in vitro acid stress and hypoxia, environments from establishment of infection and survival in granuloma, respectively. By searching for convergent evolution in gene expression across the phylogenetic tree, we will identify expression programs and genetic variants that drive adaptive change in host. In Aim 2, we will build on our discovery of ESX-1’s expression variation and integrate natural variants driving four distinct expression states across two secreted effector operons. Next, we will use these engineered strains in a macrophage and mouse model of infection to determine if and how they drive different disease phenotypes. Mtb is under constant selective pressure to survive the host environment. This work uses Mtb’s natural variation to illuminate the genetic pathways and molecular strategies that evolution bends to this goal. This work will explore the mechanisms of Mtb genetic variation that contribute to variable disease outcomes. It is critical that we expand our understanding of pathogens beyond a few strains: if we limit ourselves to laboratory strains, we risk designing treatments that will not work outside the laboratory.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $86,824 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	3	1/8/2026	NON-COMPETING CONTINUATION	$85,360
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	3	4/2/2026	NON-COMPETING CONTINUATION	$1,464
														Subtotal = $86,824

Issue Date FY: 2025 ( Subtotal = $82,744 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	2	8/12/2025	NON-COMPETING CONTINUATION	$1,380
2025	2025	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	12/19/2024	NON-COMPETING CONTINUATION	$81,364
														Subtotal = $82,744

Issue Date FY: 2024 ( Subtotal = $78,892 )
2024	2024	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	1	5/15/2024	NEW	$5,120
2024	2024	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	11/30/2023	NEW	$73,772
														Subtotal = $78,892

Grand Total All Awards = $248,460

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Dissecting virulence gene regulatory pathways in M. tuberculosis clinical isolates

Award Number: F32AI174653

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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