Project Summary/Abstract The increase in diabetes patients in countries where tuberculosis (TB) is also endemic has led to the re-emerging importance of diabetes as a serious risk factor for TB. There is an urgent need to implement strategies for TB prevention and control among the millions of diabetes patients exposed to Mycobacterium tuberculosis (Mtb), the causative agent of TB. Although diabetes is known to modulate immune responses, most of the studies on TB-diabetes comorbidity have been primarily focused on the altered functions of lymphocytes. Lung macrophages are among the first host cells that respond to Mtb and are recognized as one of the most crucial cell types in determining the consequences of disease. Our previous work has demonstrated that lung macrophage metabolism plays a critical role in promoting or controlling the progression of TB. However, whether the increased susceptibility to TB in diabetes is caused by altered metabolic activities in lung macrophages is virtually unknown, thus representing a significant knowledge gap. The phenotype and functions of tissue-resident macrophages are greatly influenced by the level of nutrients in their environmental niches. Given that diabetes induces chronic hyperglycemia, a key factor that contributes to the development of TB in diabetic conditions, we hypothesize that the altered metabolism in lung macrophages, due to the hyperglycemic environment, leads to increased susceptibility to TB in diabetes. We will test this hypothesis with two aims: Aim 1. Determine the impact of hyperglycemia on the metabolic status and permissiveness of lung AMs during Mtb infection. Aim 2. Interrogate how hyperglycemia influences the heterogeneity of lung macrophages in TB. We will use multi- disciplinary approaches, including metabolism, genomics and microbiology to interrogate the underlying mechanism of TB-diabetes comorbidity from a completely novel perspective.