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Infection and Immunity, October 2009, p. 4538-4547, Vol. 77, No. 10
0019-9567/09/$08.00+0 doi:10.1128/IAI.01256-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN
,
Nicole N. Driessen,1
Roy Ummels,1
Janneke J. Maaskant,1
Sudagar S. Gurcha,2
Gurdyal S. Besra,2
Gary D. Ainge,3,4
David S. Larsen,4
Gavin F. Painter,3
Christina M. J. E. Vandenbroucke-Grauls,1
Jeroen Geurtsen,1 and
Ben J. Appelmelk1*
Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 BT Amsterdam, The Netherlands,1 School of Biosciences, University of Birmingham, Edgbaston B15 2TT, United Kingdom,2 Carbohydrate Chemistry Team, Industrial Research Limited, Lower Hutt 5040, New Zealand,3 Department of Chemistry, University of Otago, Dunedin 9054, New Zealand4
Received 14 October 2008/ Returned for modification 8 December 2008/ Accepted 29 July 2009
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 
(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-Guérin deficient in the production of PIM6 (
pimE) was created, as well as a double knockout deficient in the production of both PIM6 and the mannose caps on LAM (pimE 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.
* Corresponding author. Present address: Department of Medical Microbiology and Infection Control, Medical Faculty, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. Phone: 31-(0)20-4448297. Fax: 31-(0)20-4448318. E-mail: bj.appelmelk{at}vumc.nl
Published ahead of print on 3 August 2009.
Supplemental material for this article may be found at http://iai.asm.org/.
Infection and Immunity, October 2009, p. 4538-4547, Vol. 77, No. 10
0019-9567/09/$08.00+0 doi:10.1128/IAI.01256-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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