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Elucidation of the molecular mechanism(s) for the non-responsiveness of CD38- AMs to tuberculosis infection

Award Number: R21AI178534
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: 06/01/2024
PERIOD OF PERFORMANCE END DATE: 10/30/2024

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Elucidation of the molecular mechanism(s) for the non-responsiveness of CD38- AMs to tuberculosis infection - The lung-resident alveolar macrophages (AMs) are the initial host cells infected by inhaled Mycobacterium tuberculosis (Mtb). While traditionally perceived as a conducive environment for Mtb replication and spread, our recent studies using fluorescent Mtb fitness reporter strains and single-cell RNA-sequencing (scRNA-seq) have revealed a more intricate reality. We discovered two primary AM populations in the Mtb-infected lung: SiglecF+ CD38+ pro-inflammatory AMs, which house stressed bacteria and express high levels of Nos2, and SiglecF+ CD38- AMs, which lack Nos2 expression and accommodate replicative bacteria. Intriguingly, our preliminary findings indicate that CD38- AMs, which exhibit limited Mtb containment capabilities, are the predominant infected AM population during the early infection stages. Moreover, intranasal BCG vaccination prior to Mtb exposure significantly reduces the number of Mtb-infected host cells and markedly increases the proportion of CD38+ infected AMs. This suggests a critical role for the CD38+ AM phenotype in triggering a protective immune response following vaccination. Although these AM subsets appear transcriptionally indistinguishable in naive mice, they demonstrate distinct chromatin organization, suggesting that epigenetic factors dictate their response to infection. Our hypothesis is that a higher prevalence of CD38+ AMs within the lung airways leads to improved early inhibition of Mtb proliferation and spread, thereby unveiling a viable avenue for immune mediate control of tuberculosis infection. Specific Aim 1: Elucidate the host molecular mechanisms contributing to the limited response of CD38- AMs to Mtb infection. To decipher the host molecular mechanisms underlying the blunted response of CD38- AMs to Mtb infection, we will employ an integrated multi-omics approach to analyze the changes in chromatin organization and transcription factor activity post-Mtb infection. We will then manipulate the AM immune environment through intranasal BCG vaccination to identify those epigenetic changes that are associated with long-term protection against Mtb infection. Specific Aim 2: Implement CRISPR-based genetic perturbation approaches in macrophages to evaluate the role of selected host responses in Mtb infection. Initially, we will use a CRISPR-based genetic perturbation approach to validate the role of candidate host genes, identified in our existing datasets, in generating pro-inflammatory macrophage responses that control Mtb infection. We will then extend this approach to functionally validate additional targets emerging from Specific Aim 1.


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 = $8,680 )
2026	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	002	3	2/23/2026	NON-COMPETING CONTINUATION	$190,526
2026	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	3	2/19/2026	NON-COMPETING CONTINUATION	-$190,526
2026	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	004	3	3/6/2026	NON-COMPETING CONTINUATION	$0
2026	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	005	1	3/11/2026	NEW	$8,680
2026	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	003	2	2/23/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$186,195
2026	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	001	2	2/19/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$186,195
														Subtotal = $8,680

Issue Date FY: 2025 ( Subtotal = $190,526 )
2025	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	003	3	8/21/2025	NON-COMPETING CONTINUATION	$190,526
2025	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	002	1	6/26/2025	NEW	$0
2025	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	001	2	5/8/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$186,195
2025	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	1	5/8/2025	NEW	-$186,195
														Subtotal = $190,526

Issue Date FY: 2024 ( Subtotal = $235,500 )
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	001	1	9/11/2024	NEW	$23,550
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	1	5/31/2024	NEW	$211,950
														Subtotal = $235,500

Grand Total All Awards = $434,706

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Elucidation of the molecular mechanism(s) for the non-responsiveness of CD38- AMs to tuberculosis infection

Award Number: R21AI178534

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: 06/01/2024

PERIOD OF PERFORMANCE END DATE: 10/30/2024

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