Elevated levels of matrix metalloproteinases reflect severity and extent of disease in tuberculosis-diabetes co-morbidity and are predominantly reversed following standard anti-tuberculosis or metformin treatment

摘要

Matrix metalloproteinases (MMPs) are considered to be key mediators of tuberculosis (TB) pathology but their role in tuberculosis - diabetes comorbidity (TB-DM) is not well understood. To study the association of MMP levels with severity and extent of disease as well as bacterial burden in TB-DM, we examined the systemic levels of MMP-1, -?2, -?3, -?7, -?8, -?9, -?10, -?12 and?-?13 in individuals with TB-DM and compared them to those with TB alone (TB) or healthy controls (HC). Circulating levels of MMP-1, -?2, -?3, -?7, -?10 and?-?12 were significantly higher in TB-DM compared to both TB and HC and MMP -13 levels were higher in comparison to HC alone. To understand the effect of standard anti-tuberculosis therapy (ATT) on these MMP levels in TB-DM, we measured the levels of MMPs at the end of treatment (post-treatment). Our findings indicate that ATT is associated with a significant reduction in the levels of MMP-1, -?2, -?3, -?8 and?-?13 post-treatment. Moreover, the levels of MMP-1, -?2, -?3, -?9 and?-?12 were significantly higher in TB-DM individuals with cavitary disease and/or bilateral disease at baseline but not post-treatment. Similarly, the levels of MMP -1, -?2, -?3 and?-?8 exhibited a significant positive relationship with bacterial burden and HbA1c levels at baseline but not post-treatment. Within the TB-DM group, those known to be diabetic before incident TB (KDM) exhibited significantly higher levels of MMP-1, -?2, -?10 and?-?12 at baseline and of MMP-1 and -3 post-treatment compared to those newly diagnosed with DM (NDM). Finally, KDM individuals on metformin treatment exhibited significantly lower levels of MMP-1, -?2, -?3, -?7, -?9 and?-?12 at baseline and of MMP-7 post-treatment. Our data demonstrate that systemic MMP levels reflect baseline disease severity and extent in TB-DM, differentiate KDM from NDM and are modulated by ATT and metformin therapy.