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Macrophage nuclear receptors, metabolism and immune effectors during health and M. tuberculosis infection

Award Number: R01AI136831
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: 08/07/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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Macrophage nuclear receptors, metabolism and immune effectors during health and M. tuberculosis infection - Project Summary/Abstract Resident alveolar macrophages (AMs) possess a unique, highly regulated immune response that remains poorly understood, especially for human AMs (HAMs). Failure to understand the molecular events underlying AM development & biology creates a critical barrier to developing new treatment strategies effective in the lung. The overall goal of this ongoing research program is to identify transcriptional regulators and pathways that dictate AM immunobiology and how these are co-opted by the host-adapted intracellular pathogen Mycobacterium tuberculosis (M.tb) to enable its survival. In the last grant cycle, the lab developed the first HAM model (alveolar macrophage-like cells, AMLs) that possesses many key features of HAMs. Armed with this new model, we aim to continue our studies of nuclear receptor (NR) function in human macrophages. NRs are critical sensors & regulators of immune functions in macrophages and other cell types. Previous grant cycle work has identified MCL-1 as an effector of the NR peroxisome proliferator-activated receptor gamma (PPAR) that is critical for M.tb growth. Combination preclinical MCL-1 & BCL-2 inhibitors robustly inhibits drug-sensitive and - resistant M.tb growth in human macrophages and a human in vitro granuloma model, demonstrating the potential efficacy of a targeted host-directed therapy (HDT) for tuberculosis (TB). Building on this success, we have now identified an emerging NR family (NR4A1,2&3), whose expression, similar to PPAR, swiftly declines after AM removal from the lung, indicating a role for the NR4A family in AM phenotype & function. Thus, the NR4A family and their downstream effectors may represent a new frontier for HDT approaches for TB. Our preliminary data indicate that NR4As are important for control of M.tb in macrophages, epithelial cells, a lung on chip (LoC) model, and in vivo in mice, and therefore may oppose PPARactivity in balancing AM immune responses. Exciting new data show that key macrophage pathways in M.tb pathogenesis regulated by NR4As include Type I interferon (IFN) signaling & apoptosis. We hypothesize that lung-specific activation of NR4A family members dampens Type I IFNs and drives apoptosis to control M.tb growth. The Specific Aims are to: 1) define the roles of NR4A family members in regulating Type I IFN-mediated responses and apoptosis during M.tb infection in vitro, 2) elucidate the protective role of NR4As in vivo using M.tb mouse models, and 3) identify novel compounds that target NR4As as potential HDTs for M.tb. HAMs, AMLs, LoC, human granuloma and mouse models will be used to define the role of NR4As & PPAR during M.tb infection using biochemical, in silico, next generation sequencing and cellular immunology techniques. Since these NRs operate in a tissue, gene and signal-specific manner, these findings open the door to a completely new set of biological pathways likely to be critical to host responses in the lung during health and M.tb infection, and will aid in developing HDTs for TB, a leading cause of death.


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 = $776,975 )
2026	2026	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	002	6	7/24/2026	NON-COMPETING CONTINUATION	$776,975
2026	2022	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	001	4	2/10/2026	NON-COMPETING CONTINUATION	$0
2026	2022	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	4	1/22/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $776,975

Issue Date FY: 2025 ( Subtotal = $906,325 )
2025	2025	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	5	7/23/2025	COMPETING CONTINUATION	$906,325
														Subtotal = $906,325

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	4	7/16/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $622,521 )
2022	2022	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	4	7/20/2022	NON-COMPETING CONTINUATION	$706,804
2022	2021	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	001	3	8/9/2022	SUPPLEMENT FOR EXPANSION	-$84,283
														Subtotal = $622,521

Issue Date FY: 2021 ( Subtotal = $825,726 )
2021	2021	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	002	3	7/30/2021	SUPPLEMENT FOR EXPANSION	$84,284
2021	2021	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	001	3	7/27/2021	NON-COMPETING CONTINUATION	$706,804
2021	2021	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	2	3/24/2021	SUPPLEMENT FOR EXPANSION	$34,638
														Subtotal = $825,726

Issue Date FY: 2020 ( Subtotal = $706,804 )
2020	2020	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	2	7/13/2020	NON-COMPETING CONTINUATION	$706,804
														Subtotal = $706,804

Issue Date FY: 2019 ( Subtotal = $736,386 )
2019	2019	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	1	8/7/2019	NEW	$736,386
														Subtotal = $736,386

Grand Total All Awards = $4,574,737

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Macrophage nuclear receptors, metabolism and immune effectors during health and M. tuberculosis infection

Award Number: R01AI136831

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: 08/07/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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