Walker, N. F., Clark, S. O., Oni, T., Andreu, N., Tezera, L., Singh, S., Saraiva, L., Pedersen, B., Kelly, D. L., Tree, J. A., D'Armiento, J. M., Meintjes, G., Mauri, F. A., Williams, A., Wilkinson, R. J., Friedland, J. S. and Elkington, P. T.
Doxycycline and HIV infection suppress tuberculosis-induced matrix metalloproteinases
American Journal of Respiratory and Critical Care Medicine, 185, (9), . (doi:10.1164/rccm.201110-1769OC).
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Rationale: Tuberculosis kills over 1.5 million people per year and standard treatment has remained unchanged for over 30 years. Tuberculosis drives matrix metalloproteinase (MMP) activity to cause immunopathology. In advanced HIV infection, tissue destruction is reduced but underlying mechanisms are poorly defined and no current anti-tuberculous therapy reduces host tissue damage. Objectives: To investigate MMP activity in tuberculosis patients with and without HIV co-infection and to determine the potential of doxycycline to inhibit MMPs and decrease pathology. Methods: Concentrations of MMPs and cytokines were analyzed by Luminex array in a prospectively recruited cohort of patients. Modulation of MMP secretion and Mycobacterium tuberculosis growth by doxycycline was studied in primary human cells and tuberculosis-infected guinea pigs. Main Results: HIV co-infection decreased MMP concentrations in induced sputum of tuberculosis patients. MMPs correlated with clinical markers of tissue damage, further implicating dysregulated protease activity in tuberculosis-driven pathology. In contrast, cytokine concentrations were no different. Doxycycline, a licensed MMP inhibitor, suppressed tuberculosis-dependent MMP-1 and -9 secretion from primary human macrophages and epithelial cells by inhibiting promoter activation. In the guinea pig model, doxycycline reduced lung tuberculosis colony forming units after eight weeks in a dose-dependent manner compared to untreated animals, and in vitro doxycycline inhibited mycobacterial proliferation. Conclusions: HIV co-infection in tuberculosis patients reduces concentrations of immunopathogenic MMPs. Doxycycline decreases MMP activity in a cellular model and suppresses mycobacterial growth in vitro and in guinea pigs. Adjunctive doxycycline therapy may reduce morbidity and mortality in tuberculosis.
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