title: Non-acylated Mycobacterium bovis glycoprotein MPB83 binds to TLR1/2 and stimulates production of matrix metalloproteinase 9.
abstract: A variety of Mycobacterium tuberculosis cell wall components induce expression of matrix metalloproteinase 9 (MMP-9) by monocytic cells and levels of MMP-9 in vivo positively correlate with severity of disease. Toll-like receptor (TLR)2 mediates cellular responses to acylated molecules but can also mediate responsiveness to diverse molecular structures, including non-acylated native viral and bacterial proteins. MPT/B-83 is a cell-associated lipoglycoprotein common to M. tuberculosis and M. bovis and an important antigen during infection of cattle. Since MPB83 is acylated and glycosylated, we investigated whether MPB83 would induce MMP-9 expression via interaction with TLR2, and assessed the contribution of the lipid, glycan and polypeptide components to its activity. Acylated peptide derived from MPB83 stimulated MMP-9 expression by human macrophage cells via interaction with both TLR2 and TLR1, but not TLR4. Lesser induction was found with secreted (non-acylated, but glycosylated) MPB83 protein purified from culture of M. bovis. Stimulation of cells with MPB83 induced TNF-α production which acted to upregulate MMP-9 expression. Surprisingly, recombinant MPB83 protein devoid of any post-translational modification also induced MMP-9 expression. Direct interaction of RecMPB83 with TLR2 was demonstrated by surface plasmon-resonance. MPB83 may act as a virulence factor through TLR2 mediated induction of MMP-9.
authors.affiliation: TB Research Group, Department of Bacteriology, Veterinary Laboratories Agency Weybridge, Addlestone, Surrey KT15, UK. m.a.chambers@vla.defra.gsi.gov.uk
authors.forename: Mark A
authors.initials: MA
authors.lastname: Chambers
authors.forename: Adam O
authors.initials: AO
authors.lastname: Whelan
authors.forename: Ralf
authors.initials: R
authors.lastname: Spallek
authors.forename: Mahavir
authors.initials: M
authors.lastname: Singh
authors.forename: Bernadette
authors.initials: B
authors.lastname: Coddeville
authors.forename: Yann
authors.initials: Y
authors.lastname: Guerardel
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Elass
mesh_terms: D000215:Acylation; D057134:Antibodies, Neutralizing; D000942:Antigens, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009163:Mycobacterium bovis / Q000378:metabolism / Q000472:pathogenicity*; D020349:Surface Plasmon Resonance; D051194:Toll-Like Receptor 1 / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C094904:MPB83 protein, Mycobacterium; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; C495342:TLR2 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D020929:Mitogen-Activated Protein Kinase Kinases; D020780:Matrix Metalloproteinase 9