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Metabolic regulation of regulatory T cells through fatty acid metabolism during viral pneumonia

Award Number: F30AI188691
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/09/2025
PERIOD OF PERFORMANCE END DATE: 09/08/2028

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Metabolic regulation of regulatory T cells through fatty acid metabolism during viral pneumonia - PROJECT SUMMARY Regulatory T cells (Tregs) are a subset of CD4+ T cells that maintain immune self-tolerance and mediate the resolution of lung injury during viral pneumonia by suppressing overexuberant inflammatory responses and facilitating tissue protection and repair. During viral infection, the lung microenvironment imposes substantial metabolic stress on Tregs. Tregs depend on mitochondrial oxidative phosphorylation, a process driven by fatty acid metabolism, to optimally exert their function. While there is evidence that Tregs have the potential to be clinically efficacious as a cellular therapy for patients with severe viral pneumonia, there is a need to ascertain the context-specific metabolic mechanisms that promote Treg function to enhance their therapeutic activity. Carnitine palmitoyltransferase I A (CPT1A), the rate-limiting enzyme in long chain fatty acid (LCFA) oxidation, imports LCFAs into the mitochondria where they are oxidized to acetyl-CoA to enter the tricarboxylic acid (TCA) cycle to drive oxidative phosphorylation. While established in the extreme microenvironment of tumors, it is unknown whether Tregs depend on LCFAs for their function during viral pneumonia and whether short chain fatty acids (SCFAs), which fuel oxidative phosphorylation by providing acetyl-CoA for TCA use, are able to sustain Treg function in LCFA-limited contexts. In preliminary experiments, we bred mice with Treg specific deletion of CPT1A (TregCPT1AKO) and challenged them intratracheally with influenza A and subcutaneously with B16F10 melanoma tumors. While TregCPT1AKO mice exhibit no signs of autoimmunity at homeostasis, they are more susceptible to mortality from severe influenza pneumonia and exhibit slower tumor progression compared with controls. These results suggest that CPT1A is dispensable to maintain homeostatic self-tolerance but is necessary for Treg function during pathologically-induced microenvironmental mitochondrial stress. Therefore, we hypothesize that Tregs require CPT1A-mediated mitochondrial LCFA metabolism to provide lung tissue protection following severe viral pneumonia. We will causally test this hypothesis by studying mice with Treg-specific deletion of CPT1A in the influenza A mouse model of viral pneumonia. Our Specific Aims are 1) to determine whether CPT1A-mediated long chain fatty acid oxidation is necessary for Treg tissue-protective function during influenza A virus pneumonia and 2) to determine whether long chain fatty acids enter the mitochondrial TCA cycle and whether short chain fatty acids are sufficient to maintain acetyl-CoA levels in and function of LCFAO-deficient lung Tregs during influenza A pneumonia. The PI will benefit from the collective intellectual and technical expertise of their mentorship committee—comprised of experts in immunology, metabolism, epigenetics, and lung disease—who will provide him with project support and mentorship throughout the funding period. The resource-rich environment afforded to the PI is equipped with all necessary facilities, equipment, and expertise to complete the research strategy and training plan.


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 = $0 )
2026	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Allergy and Infectious Diseases Research	000	1	1/6/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $53,461 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Allergy and Infectious Diseases Research	001	1	9/9/2025	NEW	$0
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Allergy and Infectious Diseases Research	000	1	9/9/2025	NEW	$53,461
														Subtotal = $53,461

Grand Total All Awards = $53,461

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Metabolic regulation of regulatory T cells through fatty acid metabolism during viral pneumonia

Award Number: F30AI188691

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/09/2025

PERIOD OF PERFORMANCE END DATE: 09/08/2028

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