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Early secretory antigenic target-6 drives matrix metalloproteinase-10 gene expression and secretion in tuberculosis

Early secretory antigenic target-6 drives matrix metalloproteinase-10 gene expression and secretion in tuberculosis
Early secretory antigenic target-6 drives matrix metalloproteinase-10 gene expression and secretion in tuberculosis
Tuberculosis (TB) causes disease worldwide, and multidrug resistance is an increasing problem. Matrix metalloproteinases (MMPs), particularly the collagenase MMP-1, cause lung extracellular matrix destruction, which drives disease transmission and morbidity. The role in such tissue damage of the stromelysin MMP-10, a key activator of the collagenase MMP-1, was investigated in direct Mycobacterium tuberculosis (Mtb)–infected macrophages and in conditioned medium from Mtb-infected monocyte–stimulated cells. Mtb infection increased MMP-10 secretion from primary human macrophages 29-fold, whereas Mtb-infected monocytes increased secretion by 4.5-fold from pulmonary epithelial cells and 10.5-fold from fibroblasts. Inhibition of MMP-10 activity decreased collagen breakdown. In two independent cohorts of patients with TB from different continents, MMP-10 was increased in both induced sputum and bronchoalveolar lavage fluid compared with control subjects and patients with other respiratory diseases (both P < 0.05). Mtb drove 3.5-fold greater MMP-10 secretion from human macrophages than the vaccine strain bacillus Calmette–Guerin (P < 0.001), whereas both mycobacteria up-regulated TNF-α secretion equally. Using overlapping, short, linear peptides covering the sequence of early secretory antigenic target-6, a virulence factor secreted by Mtb, but not bacillus Calmette–Guerin, we found that stimulation of human macrophages with a single specific 15–amino acid peptide sequence drove threefold greater MMP-10 secretion than any other peptide (P < 0.001). Mtb-driven MMP-10 secretion was inhibited in a dose-dependent manner by p38 and extracellular signal–related kinase mitogen-activated protein kinase blockade (P < 0.001 and P < 0.01 respectively), but it was not affected by inhibition of NF-κB. In summary, Mtb activates inflammatory and stromal cells to secrete MMP-10, and this is partly driven by the virulence factor early secretory antigenic target-6, implicating it in TB-associated tissue destruction.
1044-1549
223-232
Brilha, Sara
acd2a966-ffbd-4f38-92b7-9a189d13d668
Sathyamoorthy, Tarangini
0217c808-371e-4292-a33d-0082d4e681d5
Stuttaford, Laura H.
8bf3ec1c-c04e-4880-9b3f-a95cf4544f8b
Walker, Naomi F.
e586ffdf-ae4b-46fa-83a1-db72501d17c1
Wilkinson, Robert J.
efcf7079-ebfa-4270-b7a4-a578ffd91178
Singh, Shivani
2549ecbb-b814-4a3d-aa12-2eb7c0bfbc8a
Moores, Rachel C.
8932d90a-3cbe-4c07-897c-1261990f43d5
Elkington, Paul T.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Friedland, Jon S.
9968669f-afe0-4163-9b35-3b476246fd4a
Brilha, Sara
acd2a966-ffbd-4f38-92b7-9a189d13d668
Sathyamoorthy, Tarangini
0217c808-371e-4292-a33d-0082d4e681d5
Stuttaford, Laura H.
8bf3ec1c-c04e-4880-9b3f-a95cf4544f8b
Walker, Naomi F.
e586ffdf-ae4b-46fa-83a1-db72501d17c1
Wilkinson, Robert J.
efcf7079-ebfa-4270-b7a4-a578ffd91178
Singh, Shivani
2549ecbb-b814-4a3d-aa12-2eb7c0bfbc8a
Moores, Rachel C.
8932d90a-3cbe-4c07-897c-1261990f43d5
Elkington, Paul T.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Friedland, Jon S.
9968669f-afe0-4163-9b35-3b476246fd4a

Brilha, Sara, Sathyamoorthy, Tarangini, Stuttaford, Laura H., Walker, Naomi F., Wilkinson, Robert J., Singh, Shivani, Moores, Rachel C., Elkington, Paul T. and Friedland, Jon S. (2017) Early secretory antigenic target-6 drives matrix metalloproteinase-10 gene expression and secretion in tuberculosis. American Journal of Respiratory Cell and Molecular Biology, 56 (2), 223-232. (doi:10.1165/rcmb.2016-0162OC).

Record type: Article

Abstract

Tuberculosis (TB) causes disease worldwide, and multidrug resistance is an increasing problem. Matrix metalloproteinases (MMPs), particularly the collagenase MMP-1, cause lung extracellular matrix destruction, which drives disease transmission and morbidity. The role in such tissue damage of the stromelysin MMP-10, a key activator of the collagenase MMP-1, was investigated in direct Mycobacterium tuberculosis (Mtb)–infected macrophages and in conditioned medium from Mtb-infected monocyte–stimulated cells. Mtb infection increased MMP-10 secretion from primary human macrophages 29-fold, whereas Mtb-infected monocytes increased secretion by 4.5-fold from pulmonary epithelial cells and 10.5-fold from fibroblasts. Inhibition of MMP-10 activity decreased collagen breakdown. In two independent cohorts of patients with TB from different continents, MMP-10 was increased in both induced sputum and bronchoalveolar lavage fluid compared with control subjects and patients with other respiratory diseases (both P < 0.05). Mtb drove 3.5-fold greater MMP-10 secretion from human macrophages than the vaccine strain bacillus Calmette–Guerin (P < 0.001), whereas both mycobacteria up-regulated TNF-α secretion equally. Using overlapping, short, linear peptides covering the sequence of early secretory antigenic target-6, a virulence factor secreted by Mtb, but not bacillus Calmette–Guerin, we found that stimulation of human macrophages with a single specific 15–amino acid peptide sequence drove threefold greater MMP-10 secretion than any other peptide (P < 0.001). Mtb-driven MMP-10 secretion was inhibited in a dose-dependent manner by p38 and extracellular signal–related kinase mitogen-activated protein kinase blockade (P < 0.001 and P < 0.01 respectively), but it was not affected by inhibition of NF-κB. In summary, Mtb activates inflammatory and stromal cells to secrete MMP-10, and this is partly driven by the virulence factor early secretory antigenic target-6, implicating it in TB-associated tissue destruction.

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Brilha Sathyamoorthy et al AJRCMB_author accepted - Accepted Manuscript
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Accepted/In Press date: 14 September 2016
e-pub ahead of print date: 21 September 2016
Published date: 1 February 2017
Organisations: Clinical & Experimental Sciences

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Local EPrints ID: 406771
URI: https://eprints.soton.ac.uk/id/eprint/406771
ISSN: 1044-1549
PURE UUID: 416cf2e3-08c3-4ea0-b2a8-af77b9b519f1
ORCID for Paul T. Elkington: ORCID iD orcid.org/0000-0003-0390-0613

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Date deposited: 22 Mar 2017 02:08
Last modified: 10 Dec 2019 01:37

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Contributors

Author: Sara Brilha
Author: Tarangini Sathyamoorthy
Author: Laura H. Stuttaford
Author: Naomi F. Walker
Author: Robert J. Wilkinson
Author: Shivani Singh
Author: Rachel C. Moores
Author: Jon S. Friedland

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