Immune mechanisms and oxidative stress underlying the interaction of Tuberculosis and Diabetes

Type 2 diabetes (DM) is a risk factor for the development of active tuberculosis (TB).

We will explore immune mechanisms of M. tuberculosis control that underly TB-DM comorbidity.Based on definitive experimental data, we hypothesize that  methylglyoxal (MGO), a reactive carbonyl molecule and by product of glycolysis that is elevated during DM, activates the transcription factor NRF2.

NRF2 activation is mediated by MGO binding to both the thioredoxin reductase TrXR1, converting it into a NADPH oxidase, and by binding and  inhibiting KEAP1 (a sensor of oxidative stress that in normal conditions impairs NRF2 stability). M. tuberculosis infection of macrophages hamper MGO detoxification pathways, resulting in a chronic NRF2 activation.

NRF2 activation impairs the production of anti-bacterial cytokines and inflammatory mediators, resulting in an increased   intracellular growth of M. tuberculosis.

This mechanism may underly TB-DM comorbidity.Specifically, we propose to:Investigate the role of NRF2 in the MGO-mediated regulation of tuberculosis infection by inflammatory and resident alveolar macrophages.Evaluate the role of overexpression and deficiency of NRF2 in macrophages and T cells in the outcome of tuberculosis infection of diabetic or control mice.Compare the molecular landscape of lung granulomas from TB and TB-DM patients with focus in immune and NRF2 responses by spatial proteomics and transcriptomics.