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Dynamics of the cellular and molecular architecture of human pulmonary TB granulomas

Award Number: R01AI166313
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/10/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Dynamics of the cellular and molecular architecture of human pulmonary TB granulomas - PROJECT SUMMARY/ABSTRACT Immunologically, the enigma of the granuloma is best reflected in that sterile, bacillus-controlling, and progressive granulomas can coexist in the same lung, with the progressive form ultimately killing the host. This observation is consistent with the modern concept of “concomitant immunity: the paradoxical immune status in which resistance to reinfection coincides with the persistence of the original infection”. Here, we will test the hypothesis that the development of concomitant immunity regulates macrophage differentiation, influencing granuloma formation and ultimately the outcome of the battle between the immune response and the pathogen Mycobacterium tuberculosis. To do so, we will use single cell RNA sequencing and spatial sequencing to map the coordinates of cell populations and antimicrobial mediators in human TB granulomas. We propose the following specific aims: 1) elucidate the cellular and molecular architecture of human pulmonary TB granulomas, 2) investigate the role of macrophage subpopulations that contribute to the antimicrobial response vs. pathogenesis of TB granulomas; and 3) investigate the role of T cell subpopulations in contributing to concomitant immunity in TB granulomas. We will identify specific cell subpopulations that contribute to host defense by comparing individual TB granulomas with varying bacterial loads and those with pathogenesis by examining the dynamic change with the progression of primary lesions, to early lesions with bronchial obstruction, to post-primary granulomas. We will determine the role of macrophage subpopulations in host defense and pathogenesis, in particular the foamy macrophages that we discovered express TREM2. We will investigate which T cell populations are predictors of individuals that respond to chemotherapy versus those that are resistant and therefore serve as biomarkers. These studies will bring together collaborators at UCLA, the Ragon Institute and the Institut Pasteur de Tunis with expertise in clinical tuberculosis, immunology and molecular biology to gain new insight into the mechanisms by which concomitant immunity influences granuloma structure to optimize host defense against TB.


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 = $648,711 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	5	2/2/2026	SUPPLEMENT FOR EXPANSION	$115,377
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	5	1/29/2026	NON-COMPETING CONTINUATION	$533,334
														Subtotal = $648,711

Issue Date FY: 2025 ( Subtotal = $629,213 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	4	1/22/2025	NON-COMPETING CONTINUATION	$629,213
														Subtotal = $629,213

Issue Date FY: 2024 ( Subtotal = $648,711 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	3	5/23/2024	NON-COMPETING CONTINUATION	$64,871
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	1/8/2024	NON-COMPETING CONTINUATION	$583,840
														Subtotal = $648,711

Issue Date FY: 2023 ( Subtotal = $647,775 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	1/17/2023	NON-COMPETING CONTINUATION	$647,775
														Subtotal = $647,775

Issue Date FY: 2022 ( Subtotal = $674,955 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	2/9/2022	NEW	$674,955
														Subtotal = $674,955

Grand Total All Awards = $3,249,365

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Dynamics of the cellular and molecular architecture of human pulmonary TB granulomas

Award Number: R01AI166313

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/10/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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