ESAT-6 Drives MMP-10 Gene Expression and Secretion in Tuberculosis.
Brilha, S; Sathyamoorthy, T; Stuttaford, LH; Walker, NF; Wilkinson, RJ; Singh, S; Moores, RC; Elkington, PT; Friedland, JS; (2016) ESAT-6 Drives MMP-10 Gene Expression and Secretion in Tuberculosis. American journal of respiratory cell and molecular biology, 56 (2). pp. 223-232. ISSN 1044-1549 DOI: https://doi.org/10.1165/rcmb.2016-0162OC
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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.<br/>
Item Type: | Article |
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Faculty and Department: | Faculty of Infectious and Tropical Diseases > Dept of Clinical Research |
PubMed ID: | 27654284 |
Web of Science ID: | 398807300011 |
URI: | http://researchonline.lshtm.ac.uk/id/eprint/3167350 |
Available Versions of this Item
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[Accepted Manuscript] ESAT-6 Drives MMP-10 Gene Expression and Secretion in Tuberculosis. (deposited 30 Nov 2016 15:44)
- ESAT-6 Drives MMP-10 Gene Expression and Secretion in Tuberculosis. (deposited 13 Dec 2017 13:04) [Currently Displayed]
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