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Functional dynamics of TB granuloma architecture

Award Number: U01AI166309
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/18/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Functional dynamics of TB granuloma architecture - Project Summary/Abstract Understanding and eliminating TB depends on understanding the host and pathogen dynamics in granulomas, where the outcomes of M. tuberculosis infection are determined. Despite substantial efforts, the cellular composition, spatial interactions, and mechanisms that determine outcomes such as pathologic granuloma necrosis are poorly understood. One explanation for the limited understanding of granulomas is that most studies are performed in a single experimental system in isolation. We have formed a consortium to perform and integrate studies of TB granulomas in three systems: humans, rhesus macaques, and new strains of mice. In these three systems, we will address several major questions in TB granuloma biology: what is the extent of diversity in cell composition in TB granulomas? What regulates cell trafficking and spatial interactions in TB granulomas? What are the roles of type I interferons (TIIFN) and interferon gamma (IFNg) in regulating and determining cell trafficking, differentiation, spatial relationships, and activation states in TB granulomas? What are the pathogen and host determinants of necrosis, a pathologic outcome, in TB granulomas? Our primary mode for investigating these and other questions will be high-parameter multiplex immunostaining of TB granulomas from the three species, as this will provide essential insight into the spatial relationships between immune cell subsets. Multiplex immunostaining will be complemented by studies of live imaging of cell dynamics in rhesus macaque granulomas and by strategically-timed transfers of labeled cells in rhesus macaques and diverse strains of mice. The value of the multiplex immunostaining studies will be further enhanced by deep characterization of dissociated cell populations at the single-cell level, using high parameter flow cytometry and single-cell transcriptomics. A uniquely important contribution of our proposed project is the computational integration of data from humans, rhesus macaques, and new strains of mice. By integrating multispecies data, we will identify the features of TB granulomas that are common to all three species, and we will identify factors that are unique to granulomas in each species, to guide further modifications to improve the utility of studies in animal models. Integration of the data from the three species will allow studies in rhesus macaques to be compared with those of human samples and new strains of mice; this will improve the understanding and interpretation of human pathology studies, and enhance the value of studies that can take advantage of using the unique advantages of mice for mechanistic studies. Together, our studies will advance the knowledge and understanding of TB biology, and guide development of interventions to improve treatment outcomes, limit lung damage, and improve lung tissue repair in people suffering from 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 = $59,260 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	5	2/12/2026	SUPPLEMENT FOR EXPANSION	$59,260
														Subtotal = $59,260

Issue Date FY: 2025 ( Subtotal = $676,942 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	002	4	8/6/2025	NON-COMPETING CONTINUATION	$617,682
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	003	4	8/7/2025	SUPPLEMENT FOR EXPANSION	$59,260
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	3	7/9/2025	OTHER REVISION	$0
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	3	4/21/2025	TERMINATION	$0
														Subtotal = $676,942

Issue Date FY: 2024 ( Subtotal = $649,879 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	3	2/29/2024	NON-COMPETING CONTINUATION	$554,643
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	002	3	8/7/2024	SUPPLEMENT FOR EXPANSION	$33,610
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	3	5/23/2024	NON-COMPETING CONTINUATION	$61,626
														Subtotal = $649,879

Issue Date FY: 2023 ( Subtotal = $615,683 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	2	2/23/2023	NON-COMPETING CONTINUATION	$615,683
2023	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	1	1/5/2023	NEW	$0
														Subtotal = $615,683

Issue Date FY: 2022 ( Subtotal = $623,757 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	1	3/17/2022	NEW	$623,757
														Subtotal = $623,757

Grand Total All Awards = $2,625,521

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Functional dynamics of TB granuloma architecture

Award Number: U01AI166309

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 03/18/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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