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Abstract
BackgroundMatrix 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.MethodsTo 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).ResultsCirculating 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.ConclusionsOur 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.
Highlights
Matrix metalloproteinases (MMPs) are considered to be key mediators of tuberculosis (TB) pathology but their role in tuberculosis – diabetes comorbidity (TB-diabetes mellitus (DM)) is not well understood
Heightened levels of circulating MMPs in tuberculosis – diabetes comorbidity (TB-DM) and reversal following anti-tuberculosis therapy (ATT) As MMPs are linked with inflammation and tissue damage as well as matrix remodelling in TB, we wanted to examine the systemic levels of circulating MMPs in TB-DM, TB and healthy controls (HC) individuals
To study the effect of ATT on MMP levels in TB-DM, we measured the levels of MMPs in TB-DM before and at the end of ATT
Summary
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. MMPs play a substantial role in diverse biological functions involving many characteristics of the immune response [2, 3]. Previous studies have demonstrated that MMP levels are increased in human TB and correlate strongly with clinical and radiological markers of lung tissue destruction [4]. In spite of crucial role of MMPs in lung matrix destruction in human TB, the principal mechanisms resulting in tissue damage have not been defined. Since TB-DM is characterized by increased immune pathology compared to TB alone [6, 9], we postulated that one potential mechanism could be a systemic expansion in the levels of MMPs in TB-DM individuals
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