Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN

N.N. Driessen, R. Ummels, J.J. Maaskant, S.S. Gurcha, G.S. Besra, G.D. Ainge, D.S. Larsen, G.F. Painter, C.M.J.E. Vandenbroucke-Grauls, J.J.G. Geurtsen, B.J. Appelmelk

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The C-type lectin dendritic cell (DC)-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is the major receptor on DCs for mycobacteria of the Mycobacterium tuberculosis complex. Recently, we have shown that although the mannose caps of the mycobacterial surface glycolipid lipoarabinomannan (ManLAM) are essential for the binding to DC-SIGN, genetic removal of these caps did not diminish the interaction of whole mycobacteria with DC-SIGN and DCs. Here we investigated the role of the structurally related glycolipids phosphatidylinositol mannosides (PIMs) as possible ligands for DC-SIGN. In a binding assay with both synthetic and natural PIMs, DC-SIGN exhibited a high affinity for hexamannosylated PIM6, which contains terminal alpha(1 -> 2)-linked mannosyl residues identical to the mannose cap on ManLAM, but not for di- and tetramannosylated PIM2 and PIM4, respectively. To determine the role of PIM6 in the binding of whole mycobacteria to DC-SIGN, a mutant strain of M. bovis bacillus Calmette-Guerin deficient in the production of PIM6 (Delta pimE) was created, as well as a double knockout deficient in the production of both PIM6 and the mannose caps on LAM (Delta pimE Delta capA). Compared to the wild-type strain, both mutant strains bound similarly well to DC-SIGN and DCs. Furthermore, the wild-type and mutant strains induced comparable levels of interleukin-10 and interleukin-12p40 when used to stimulate DCs. Hence, we conclude that, like ManLAM, PIM6 represents a bona fide DC-SIGN ligand but that other, as-yet-unknown, ligands dominate in the interaction between mycobacteria and DCs
Original languageUndefined/Unknown
Pages (from-to)4538-4547
JournalInfection and Immunity
Issue number10
Publication statusPublished - 2009

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