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Doxycycline and HIV infection suppress tuberculosis-induced matrix metalloproteinases

Doxycycline and HIV infection suppress tuberculosis-induced matrix metalloproteinases
Doxycycline and HIV infection suppress tuberculosis-induced matrix metalloproteinases
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.
1073-449X
989-997
Walker, N. F.
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Clark, S. O.
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Oni, T.
6699293e-9c40-4784-ab6c-a4e55a7649cc
Andreu, N.
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Tezera, L.
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Singh, S.
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Saraiva, L.
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Pedersen, B.
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Kelly, D. L.
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Tree, J. A.
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D'Armiento, J. M.
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Meintjes, G.
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Mauri, F. A.
398755aa-4a77-41a2-8e01-f5ef04206783
Williams, A.
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Wilkinson, R. J.
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Friedland, J. S.
9dd800b0-70cb-4793-988f-a24e387b4e46
Elkington, P. T.
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Walker, N. F.
1e4bfd27-2a47-4b61-979a-98fd0274e8fa
Clark, S. O.
211ed3d8-e78d-4520-ba61-476bef749b40
Oni, T.
6699293e-9c40-4784-ab6c-a4e55a7649cc
Andreu, N.
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Tezera, L.
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Singh, S.
a9cd7e50-e572-4cba-a98d-f3f73372097b
Saraiva, L.
a44071de-689c-4a91-bff0-708ccefd3908
Pedersen, B.
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Kelly, D. L.
41a1f86f-4a93-41d7-b144-e48ff7c8f905
Tree, J. A.
7294d87c-a6f1-4319-828a-11bfd126501a
D'Armiento, J. M.
021f89d4-17e8-4023-a2c0-8188a801d439
Meintjes, G.
3ddec2e1-5c8b-420c-8d07-9c8751e78c53
Mauri, F. A.
398755aa-4a77-41a2-8e01-f5ef04206783
Williams, A.
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Wilkinson, R. J.
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Friedland, J. S.
9dd800b0-70cb-4793-988f-a24e387b4e46
Elkington, P. T.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15

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), 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

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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 Feb 2021 17:19

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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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