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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 &lt; 0.05). Mtb drove 3.5-fold greater MMP-10 secretion from human macrophages than the vaccine strain bacillus Calmette-Guerin (P &lt; 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 &lt; 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 &lt; 0.001 and P &lt; 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
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

• [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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