Role of phosphatidylinositol mannosides in the interaction between mycobacteria and DC-SIGN.
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 PIM(6), which contains terminal alpha(1-->2)-linked mannosyl residues identical to the mannose cap on ManLAM, but not for di- and tetramannosylated PIM(2) and PIM(4), respectively. To determine the role of PIM(6) in the binding of whole mycobacteria to DC-SIGN, a mutant strain of M. bovis bacillus Calmette-Guérin deficient in the production of PIM(6) (Delta pimE) was created, as well as a double knockout deficient in the production of both PIM(6) 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, PIM(6) represents a bona fide DC-SIGN ligand but that other, as-yet-unknown, ligands dominate in the interaction between mycobacteria and DCs.
Driessen
Nicole N
NN
Department of Medical Microbiology and Infection Control, Medical Faculty, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
Ummels
Roy
R
Maaskant
Janneke J
JJ
Gurcha
Sudagar S
SS
Besra
Gurdyal S
GS
Ainge
Gary D
GD
Larsen
David S
DS
Painter
Gavin F
GF
Vandenbroucke-Grauls
Christina M J E
CM
Geurtsen
Jeroen
J
Appelmelk
Ben J
BJ
D001422:Bacterial Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology*; D017353:Gene Deletion; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism*; D009163:Mycobacterium bovis / Q000235:genetics / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D016753:Interleukin-10; D053762:Interleukin-12 Subunit p40; D037181:Lectins, C-Type; D010716:Phosphatidylinositols; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C034154:phosphatidylinositol mannoside