Chaudhary, S.; Sravya, M.; Pahwa, F.; V, S.; Singh, P.; Chaturvedi, S.; Mohanty, D.; Dash, D.; Nanda, R.

Understanding the perturbed lung immune cell distribution and their functionality in tuberculosis is well documented; however, limited reports covered their disruption, if any, in diabetes-tuberculosis (DM-TB) comorbid conditions. Here, we measured serum cytokines and employed single-cell RNA-seq to investigate the molecular mechanisms that govern the heterogeneity in host immune response in DM TB comorbid conditions. Diabetes associated with chronic hyperinflammation and reduced lung infiltrating immune cells delayed the immune response to Mycobacterial infection. scRNA-seq of lung CD3+ and CD11c+ cells revealed compromised adaptive and innate immunity, with decreased Th1 and M1 macrophage populations in DM-TB mice. A dampened immune response, marked by increased IL-16 signaling and reduced TNF and IFN-II responses observed in DM-TB. This study highlights chronic inflammation, hyperglycemia, and dyslipidemia associated with diabetes impairing anti-TB immunity, and selective inhibition of aberrant IL-16 secretion and Th17 cell activation might provide strategies for better management of this comorbidity.