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Doxycycline and HIV infection suppress tuberculosis-induced matrix metalloproteinases

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. (2012) Doxycycline and HIV infection suppress tuberculosis-induced matrix metalloproteinases American Journal of Respiratory and Critical Care Medicine, 185, (9), pp. 989-997. (doi:10.1164/rccm.201110-1769OC).

Record type: Article

Abstract

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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Published date: February 2012
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 340673
URI: http://eprints.soton.ac.uk/id/eprint/340673
ISSN: 1073-449X
PURE UUID: a55a3622-6516-4c04-9a8b-1852fa558755
ORCID for P. T. Elkington: ORCID iD orcid.org/0000-0003-0390-0613

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Date deposited: 28 Jun 2012 13:53
Last modified: 18 Jul 2017 05:42

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Contributors

Author: N. F. Walker
Author: S. O. Clark
Author: T. Oni
Author: N. Andreu
Author: L. Tezera
Author: S. Singh
Author: L. Saraiva
Author: B. Pedersen
Author: D. L. Kelly
Author: J. A. Tree
Author: J. M. D'Armiento
Author: G. Meintjes
Author: F. A. Mauri
Author: A. Williams
Author: R. J. Wilkinson
Author: J. S. Friedland
Author: P. T. Elkington ORCID iD

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