title: Overexpression of proinflammatory TLR-2-signalling lipoproteins in hypervirulent mycobacterial variants.
abstract: Changes in the cell envelope composition of mycobacteria cause major changes in cytokine profiles of infected antigen presenting cells. We describe here the modulation of inflammatory responses by Mycobacterium abscessus, an emerging pathogen in cystic fibrosis. M. abscessus is able to switch from a smooth (S) to a rough (R) morphotype by the loss of a surface glycopeptidolipid. R variants are associated with severe clinical forms and a 'hyper-proinflammatory' response in ex vivo and in vivo models. Using partitioning of cell surface components we found that a complex fraction, more abundant in R variants than in S variants, made a major contribution to the TLR-2-dependent hyper-proinflammatory response induced by R variants. Lipoproteins were the main TLR-2 agonists in this fraction, consistent with the larger amounts of 16 lipoproteins in cell surface extracts from R variants; 15 out of 16 being more strongly induced in R variant than in S variant. Genetic interruption of glycopeptidolipid pathway in wild-type S variant resulted in R phenotype with similar induction of lipoprotein genes. In conclusion, R morphotype in M. abscessus is associated with increased synthesis/exposure at the cell surface of lipoproteins, these changes profoundly modifying the innate immune response through TLR-2-dependent mechanisms.
authors.affiliation: EA 3647 Physiopathologie et diagnostic des infections microbiennes, Université Versailles St Quentin, and Laboratoire de Microbiologie, Hôpital Raymond Poincaré, AP-HP, Garches, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Roux
authors.forename: Aurélie
authors.initials: A
authors.lastname: Ray
authors.forename: Alexandre
authors.initials: A
authors.lastname: Pawlik
authors.forename: Halima
authors.initials: H
authors.lastname: Medjahed
authors.forename: Gilles
authors.initials: G
authors.lastname: Etienne
authors.forename: Martin
authors.initials: M
authors.lastname: Rottman
authors.forename: Emilie
authors.initials: E
authors.lastname: Catherinot
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Coppée
authors.forename: Karima
authors.initials: K
authors.lastname: Chaoui
authors.forename: Bernard
authors.initials: B
authors.lastname: Monsarrat
authors.forename: Antoine
authors.initials: A
authors.lastname: Toubert
authors.forename: Mamadou
authors.initials: M
authors.lastname: Daffé
authors.forename: Germain
authors.initials: G
authors.lastname: Puzo
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Gaillard
authors.forename: Roland
authors.initials: R
authors.lastname: Brosch
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dulphy
authors.forename: Jérôme
authors.initials: J
authors.lastname: Nigou
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Herrmann
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005455:Fluorescent Antibody Technique; D006020:Glycopeptides / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008074:Lipoproteins / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages; D051379:Mice; D009161:Mycobacterium / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity; D009164:Mycobacterium Infections / Q000276:immunology / Q000382:microbiology; D010641:Phenotype; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism*; D014774:Virulence
chemical_list: D016207:Cytokines; D006020:Glycopeptides; D008074:Lipoproteins; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2