The cell surface receptor DC-SIGN discriminates between Mycobacterium species through selective recognition of the mannose caps on lipoarabinomannan.
Interactions between dendritic cells (DCs) and Mycobacterium tuberculosis, the etiological agent of tuberculosis, most likely play a key role in anti-mycobacterial immunity. We have recently shown that M. tuberculosis binds to and infects DCs through ligation of the DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and that M. tuberculosis mannose-capped lipoarabinomannan (ManLAM) inhibits binding of the bacilli to the lectin, suggesting that ManLAM might be a key DC-SIGN ligand. In the present study, we investigated the molecular basis of DC-SIGN ligation by LAM. Contrary to what was found for slow growing mycobacteria, such as M. tuberculosis and the vaccine strain Mycobacterium bovis bacillus Calmette-Guérin, our data demonstrate that the fast growing saprophytic species Mycobacterium smegmatis hardly binds to DC-SIGN. Consistent with the former finding, we show that M. smegmatis-derived lipoarabinomannan, which is capped by phosphoinositide residues (PILAM), exhibits a limited ability to inhibit M. tuberculosis binding to DC-SIGN. Moreover, using enzymatically demannosylated and chemically deacylated ManLAM molecules, we demonstrate that both the acyl chains on the ManLAM mannosylphosphatidylinositol anchor and the mannooligosaccharide caps play a critical role in DC-SIGN-ManLAM interaction. Finally, we report that DC-SIGN binds poorly to the PILAM and uncapped AraLAM-containing species Mycobacterium fortuitum and Mycobacterium chelonae, respectively. Interestingly, smooth colony-forming Mycobacterium avium, in which ManLAM is capped with single mannose residues, was also poorly recognized by the lectin. Altogether, our results provide molecular insight into the mechanisms of mycobacteria-DC-SIGN interaction, and suggest that DC-SIGN may act as a pattern recognition receptor and discriminate between Mycobacterium species through selective recognition of the mannose caps on LAM molecules.
Maeda
Norihiro
N
Institut Pasteur, Unité de Génétique Mycobactérienne, 28 rue du Dr Roux, 75724 Paris Cedex 15, France.
Nigou
Jérôme
J
Herrmann
Jean-Louis
JL
Jackson
Mary
M
Amara
Ali
A
Lagrange
Philippe Henri
PH
Puzo
Germain
G
Gicquel
Brigitte
B
Neyrolles
Olivier
O
D015815:Cell Adhesion Molecules / Q000378:metabolism*; D003713:Dendritic Cells / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D037181:Lectins, C-Type / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism*; D008358:Mannose / Q000378:metabolism*; D009161:Mycobacterium / Q000145:classification / Q000502:physiology*; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D014162:Transfection; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D008358:Mannose; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C050016:lipoarabinomannan