Glutathione depletion in the CNS and its effects on Mtb infection

This research project supported by an Academic Research Enhancement Awards (AREA) grant from the U.S. Department of Health and Human Services to investigate the relationship between type 2 diabetes mellitus (T2DM), glutathione (GSH) depletion in the central nervous system, and susceptibility to Mycobacterium tuberculosis (Mtb) infection. The project responds to accumulating clinical observations over the past decade and a half indicating that individuals with T2DM are at increased risk for tuberculosis, a major global infectious disease burden: approximately 10 million new active TB cases and 1.6 million deaths were reported worldwide in 2017. This research proposal centers on testing whether a deficiency of GSH in the context of T2DM impairs the formation of granulomas and weakens granulomatous effector responses that contain and control Mtb, thereby creating conditions that favor bacterial replication and progression to active disease.

This research aims to clarify a specific mechanistic link between metabolic disease and infectious susceptibility by focusing on GSH, a critical intracellular antioxidant and immune-modulatory molecule. By interrogating how GSH insufficiency affects the cellular and tissue-level immune architecture critical for tuberculosis control—the granuloma—This work seeks to delineate how T2DM-associated biochemical changes can undermine host defenses against Mtb. Findings from the study are intended to inform whether GSH supplementation could be protective for individuals with T2DM and reduce their risk of developing active TB. Such an outcome would have translational importance: if GSH repletion can restore effective granulomatous responses or otherwise limit bacterial replication, it could point toward adjunctive nutritional or pharmacologic strategies to reduce TB incidence among people with diabetes.

Overall, the project positions GSH biology at the center of an investigation into a clinically observed epidemiologic link between T2DM and TB. By testing the hypothesis that GSH deficiency impairs granuloma formation and effector responses to Mtb, the research aims to generate mechanistic insight and to evaluate the potential of GSH supplementation as a protective strategy for at-risk diabetic populations. The work could contribute to new approaches for preventing active TB in people with T2DM and strengthen the evidence base for targeted interventions addressing the intersection of metabolic and infectious disease.