Macrophages of diabetes and tuberculosis co-morbid conditions show perturbed differentiation and metabolic signatures

Abstract

Diabetes negatively impacts the host immune system, leading to allergies, recurring infections, and lameness. Its impact on the distribution and molecular phenotypes of the bone marrow-derived macrophages (BMDMs) needs attention and, more importantly, in co-morbid conditions like diabetes and tuberculosis (DM-TB). In this study, total bone marrow cells were harvested at 3 w.p.i., from the low aerosol dose (100-120 CFU) of Mycobacterium tuberculosis H37Rv infected control and NA-STZ induced diabetic C57BL/6 mice. The bone marrow cells were differentiated into BMDMs, and CD11c, CD11b and F4/80 marker expressions were monitored using flow cytometry. BMDMs stimulated with Mtb H37Rv lysate were subjected to global transcriptome profiling to identify the perturbed metabolic and molecular landscape. The BMDMs of the DM-TB comorbid mice showed low CD11c, CD11b and higher F4/80 expression. The macrophages of the DM group showed a skewed pro-inflammatory response, characterized by perturbed complement response, NF-kB pathway and fatty acid metabolism, whereas macrophages of the DM-TB group showed deregulated ceramide and amino acid metabolism. Macrophages from the DM and DM-TB group stimulated with Mtb H37Rv lysate, showed a deregulated transcript signature that impacts humoral response. The dampened immune response observed in the DM-TB group macrophages highlights the importance of identifying novel targets for developing tailored drugs for comorbid conditions.