Effects of type 2 diabetes mellitus on fibrosis formation in post-tuberculosis lung disease 2259589

Abstract Introduction Tuberculosis disease (TB) is a significant global health challenge, affecting 10 million people and causing 1.3 million deaths annually. While most Mycobacterium tuberculosis (Mtb) infections resolve without causing disease, some cause residual lung damage that can lead to fibrosis. People with type 2 diabetes mellitus (T2DM) are more susceptible to Mtb infection and have worse TB outcomes, including exacerbated post-tuberculosis lung disease (PTLD). T2DM-mediated mechanisms for fibrosis formation in PTLD have not yet been fully characterized. Methods C3HeB/FeJ mice were used to induce T2DM using a combination of a high fat diet and streptozocin. Both T2DM and non-T2DM mice were infected with 102 CFU Mtb for 8 weeks prior to receiving TB chemotherapy. Samples were obtained at 8 weeks post-infection (p.i.) and 16 weeks p.i. (at end of treatment) for histological, immunological, and western blot analysis. Whole body plethysmography was performed at 4 week intervals throughout the study to determine changes in lung function over time. Results C3HeB/FeJ mice developed T2DM as determined by blood glucose level monitoring. During TB treatment, mice with T2DM showed higher levels of pro-fibrotic cytokines (e.g. IL-17A) and altered lung function in comparison to non-T2DM mice. Additionally, expression of latent TGFβ and proteins involved in TGFβ-mediated pathways affecting fibroblasts differed between groups. Histology revealed differences in granuloma formation and collagen accumulation between T2DM and non-T2DM mice. Conclusion These results indicate that T2DM affects pro-inflammatory drivers of fibrosis formation, resulting in significant physiological differences. The C3HeB/FeJ mouse shows potential as a translational model to examine the underlying mechanisms of fibrosis formation in PTLD, including as exacerbated by T2DM. Funding Source Institute for Human Infections and Immunity and Center on Lung Disease, Inflammation, and Remodeling Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)