NIH grant: Cognate CD4+ T cell help to macrophages during tuberculosis (1K22AI192592-01)

retained text

NIH grant 1K22AI192592-01: Cognate CD4+ T cell help to macrophages during tuberculosis
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Samuel Harrison Becker. Award: $161774.
Start: 2026-07-17T00:00:00.
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.

document fetched 2026-07-26 08:23