Journal Article

Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases

Pedersen, Bernadette, Williams, Ann, Wilkinson, Robert J., Friedland, Jon S., Tezera, Liku, Saraiva, Luísa, Meintjes, Graeme, D'Armiento, Jeanine M., Tree, Julia A., Walker, Naomi F., Clark, Simon O., Oni, Tolu, Kelly, Dominic L., Singh, Shivani, Andreu, Nuria, Elkington, Paul T., Mauri, Francesco A.

2012

Overview

Abstract Rationale Tuberculosis kills more than 1.5 million people per year, and standard treatment has remained unchanged for more than 30 years. Tuberculosis (TB) 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 antituberculous therapy reduces host tissue damage. Objectives To investigate MMP activity in patients with TB with and without HIV coinfection 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 TB-infected guinea pigs. Measurements and Main Results HIV coinfection decreased MMP concentrations in induced sputum of patients with TB. MMPs correlated with clinical markers of tissue damage, further implicating dysregulated protease activity in TB-driven pathology. In contrast, cytokine concentrations were no different. Doxycycline, a licensed MMP inhibitor, suppressed TB-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 TB colony forming units after 8 weeks in a dose-dependent manner compared with untreated animals, and in vitro doxycycline inhibited mycobacterial proliferation. Conclusions HIV coinfection in patients with TB 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 TB.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Adult / Aerosols / Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy / Animals / Anti-Bacterial Agents - pharmacology / Anti-Bacterial Agents - therapeutic use / Biological and medical sciences / CD4 Lymphocyte Count / Chemokines / Cytokines / Cytokines - analysis / Doxycycline - pharmacology / Doxycycline - therapeutic use / Extracellular matrix / Guinea Pigs / HIV / HIV Infections - complications / HIV Infections - enzymology / Human immunodeficiency virus / Human viral diseases / Humans / Infections / Infectious diseases / Intensive care medicine / Macrophages - drug effects / Macrophages - enzymology / Matrix Metalloproteinase 1 - metabolism / Matrix Metalloproteinase 2 - metabolism / Matrix Metalloproteinase 3 - metabolism / Matrix Metalloproteinase 8 - metabolism / Matrix Metalloproteinases - drug effects / Matrix Metalloproteinases - metabolism / Medical sciences / Middle Aged / Mortality / Mycobacterium tuberculosis - drug effects / Pathology / Probiotics / Sputum - chemistry / Sputum - enzymology / Tuberculosis / Tuberculosis, Pulmonary - complications / Tuberculosis, Pulmonary - enzymology / Viral diseases / Viral diseases of the lymphoid tissue and the blood. Aids / Young Adult