Structural determination and Toll-like receptor 2-dependent proinflammatory activity of dimycolyl-diarabino-glycerol from Mycobacterium marinum


Although it was identified in the cell wall of several pathogenic mycobacteria, the biological properties of dimycolyl-diarabino-glycerol have not been documented yet. In this study an apolar glycolipid, presumably corresponding to dimycolyl-diarabino-glycerol, was purified from Mycobacterium marinum and subsequently identified as a 5-O-mycolyl-β-Araf-(1→2)-5-O-mycolyl-α-Araf-(1→1′)-glycerol (designated Mma_DMAG) using a combination of nuclear magnetic resonance spectroscopy and mass spectrometry analyses. Lipid composition analysis revealed that mycolic acids were dominated by oxygenated mycolates over α-mycolates and devoid of trans-cyclopropane functions. Highly purified Mma_DMAG was used to demonstrate its immunomodulatory activity. Mma_DMAG was found to induce the secretion of proinflammatory cytokines (TNF-α, IL-8, IL-1β) in human macrophage THP-1 cells and to trigger the expression of ICAM-1 and CD40 cell surface antigens. This activation mechanism was dependent on TLR2, but not on TLR4, as demonstrated by (i) the use of neutralizing anti-TLR2 and -TLR4 antibodies and by (ii) the detection of secreted alkaline phosphatase in HEK293 cells co-transfected with the human TLR2 and secreted embryonic alkaline phosphatase reporter genes. In addition, transcriptomic analyses indicated that various genes encoding proinflammatory factors were up-regulated after exposure of THP-1 cells to Mma_DMAG. Importantly, a wealth of other regulated genes related to immune and inflammatory responses, including chemokines/cytokines and their respective receptors, adhesion molecules, and metalloproteinases, were found to be modulated by Mma_DMAG. Overall, this study suggests that DMAG may be an active cell wall glycoconjugate driving host-pathogen interactions and participating in the immunopathogenesis of mycobacterial infections.


Elisabeth Elass-Rochard1,2, Yoann Rombouts1,2, Bernadette Coddoveille1,2, Emmanuel Maes1,2, Renaud Belvaque3, David Hot3, Laurent Kremer4,5, Yann Guérardel1,2

  • 1. Université Lille Nord de France, Université Lille1, Unité de Glycobiologie Structurale et Fonctionnelle, UGSF, IFR 147
  • 2. CNRS, UMR 8576, F-59650 Villeneuve d’Ascq, France
  • 3. Laboratoire Transcriptomique et Génomique Appliquée, Centre d’Infection et d’Immunité de Lille-Institut Pasteur de Lille, U1019, UMR 8204, 1 rue du professeur Calmette, F-29019 Lille, France,
  • 4. Laboratoire de Dynamique des Interactions Membranaires Normales et Pathologiques (DIMMP), Université de Montpellier II et I, CNRS UMR 5235, case 107
  • 5. INSERM, DIMNP, Place Eugène Bataillon, 34095 Montpellier Cedex 05, France


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