The mannose cap of mycobacterial lipoarabinomannan does not dominate the Mycobacterium–host interaction

B.J. Appelmelk, J. Dunnen, N.N. Driessen, R. Ummels, M. Pak, J. Nigou, G. Larrouy-Maumus, S.S. Gurcha, F. Movahedzadeh, J. Geurtsen, E.J. Brown, M.M.E. Smeets, G.S. Besra, P.T.J. Willemsen, T.L. Lowary, Y. van Kooyk, J.J. Maaskant, N.G. Stoker, P. de Ley, G. PuzoC.M.J.E. Vandenbroucke-Grauls, C.W. Wieland, T. van der Poll, T.B.H. Geijtenbeek, A.M. van der Sar, W. Bitter

    Research output: Contribution to journalArticleAcademicpeer-review

    88 Citations (Scopus)

    Abstract

    Pathogenic mycobacteria have the ability to persist in phagocytic cells and to suppress the immune system. The glycolipid lipoarabinomannan (LAM), in particular its mannose cap, has been shown to inhibit phagolysosome fusion and to induce immunosuppressive IL-10 production via interaction with the mannose receptor or DC-SIGN. Hence, the current paradigm is that the mannose cap of LAM is a crucial factor in mycobacterial virulence. However, the above studies were performed with purified LAM, never with live bacteria. Here we evaluate the biological properties of capless mutants of Mycobacterium marinum and M. bovis BCG, made by inactivating homologues of Rv1635c. We show that its gene product is an undecaprenyl phosphomannose-dependent mannosyltransferase. Compared with parent strain, capless M. marinum induced slightly less uptake by and slightly more phagolysosome fusion in infected macrophages but this did not lead to decreased survival of the bacteria in vitro, nor in vivo in zebra fish. Loss of caps in M. bovis BCG resulted in a sometimes decreased binding to human dendritic cells or DC-SIGN-transfected Raji cells, but no differences in IL-10 induction were observed. In mice, capless M. bovis BCG did not survive less well in lung, spleen or liver and induced a similar cytokine profile. Our data contradict the current paradigm and demonstrate that mannose-capped LAM does not dominate the Mycobacterium-host interaction.
    Original languageEnglish
    Pages (from-to)930-944
    JournalCellular Microbiology
    Volume10
    Issue number4
    DOIs
    Publication statusPublished - 2008

    Keywords

    • human dendritic cells
    • dc-sign
    • arabinan biosynthesis
    • intracellular survival
    • transferase-activity
    • tuberculosis
    • receptor
    • binding
    • galactofuranosyltransferase
    • mannosyltransferases

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