Doxycycline and HIV infection suppress tuberculosis-induced matrix metalloproteinases

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

97 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)989-997
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume185
Issue number9
DOIs
Publication statusPublished - 1 May 2012

Keywords

  • Immunopathology
  • Lung
  • Mycobacteria
  • Protease inhibitors

Fingerprint

Dive into the research topics of 'Doxycycline and HIV infection suppress tuberculosis-induced matrix metalloproteinases'. Together they form a unique fingerprint.

Cite this