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Cognate CD4+ T cell help to macrophages during tuberculosis

Award Number: K22AI192592
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/17/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Cognate CD4+ T cell help to macrophages during tuberculosis - Project Summary Tuberculosis, caused by the phagosomal bacterial pathogen Mycobacterium tuberculosis (Mtb), is the most widespread bacterial disease among humans and the number one cause of mortality by an infection. Efforts to combat tuberculosis have been hampered by the lack of an effective vaccine, burdensome treatment regimens and drug resistance. Thus, a deeper understanding of the immune mechanisms that restrict Mtb growth or survival within the host is necessary to develop more effective therapies. Mtb preferentially infects monocyte- derived macrophages (MDMs) in the lungs. In humans and mice, CD4+ T cells are required for protection against lethal Mtb infection. In preliminary work, I demonstrated that CD4+ T cells must engage in cognate MHCII- mediated interactions with MDMs to promote their disinfection and therefore clearance of Mtb from the lungs. MHCII-deficient MDMs were defective in the expression of genes promoting glycolysis, a metabolic state that is known to promote Mtb control within macrophages. These observations therefore begin to explain how CD4+ T cells respond to and attempt to eliminate Mtb. Experiments in this proposal will extend upon my earlier work by identifying the molecular mechanisms that explain cognate CD4+ T cell help to MDMs. I will test the hypothesis that activation of CD40 on the MDM surface by CD40 ligand-expressing cognate CD4+ T cells is the signal that induces glycolytic gene expression in the MDMs. I will determine if CD40 agonism is sufficient to induce glycolytic metabolism in infected MDMs. To understand how MDM glycolysis results in disinfection, I will test the hypothesis that toxic aldehydes generated by glycolysis restrict the growth of Mtb within CD4+ T cell-helped MDMs. Mtb gene expression will be measured in vivo to identify bacterial stress response pathways, including aldehyde detoxification systems, that are induced upon cognate CD4+ T cell help. An Mtb mutagenesis screen will also be conducted to identify genes involved in aldehyde defense that required for bacterial survival in CD4+ T cell- helped MDMs. These experiments will be performed in collaboration with Dr. Jesse Williams, an expert in macrophage biology, and Dr. Anthony Baughn, who has extensive experience with Mtb mutagenesis screens. These studies should be highly impactful in part because they establish a functional immune role for cognate CD4+ T cell help to macrophages, which has not been described previously. Moreover, these studies should inform the development of therapies to treat tuberculosis because they identify host and bacterial factors associated with protection.


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 = $161,774 )
2026	2026	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	7/17/2026	NEW	$161,774
														Subtotal = $161,774

Grand Total All Awards = $161,774

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Cognate CD4+ T cell help to macrophages during tuberculosis

Award Number: K22AI192592

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/17/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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