Chronic hyperglycemia induces macrophage iron accumulation and promotes Mycobacterium tuberculosis virulence

Tuberculosis-diabetes comorbidity represents significant global health challenges, though the underlying mechanisms remain poorly understood. Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis, has a very high requirement of iron and its availability is a determining factor for successful establishment of infection. Host innate immune system and macrophages attempt to limit iron availability to restrict bacterial growth. We investigated the relationship between hyperglycemia and intracellular iron dynamics during infection using, THP-1-derived and primary macrophages from diabetic mice maintained under high-glucose conditions. Both showed increased intracellular iron along with higher expression of iron uptake receptors. Bacteria inside macrophages also contained more iron. Iron chelation significantly reduced M.tb burden in the lungs and spleen of infected diabetic mice. These findings suggest that hyperglycemia creates a "glucose legacy" that promotes iron accumulation, thereby increasing host susceptibility to M.tb infection, and reveals iron chelation as a promising adjunct therapeutic strategy.