Identification of the mycobacterial carbohydrate structure that binds the C-type lectins DC-SIGN, L-SIGN and SIGNR1.
Mycobacterium tuberculosis represents a worldwide health risk and although macrophages are primarily infected, dendritic cells (DC) are important in inducing cellular immune responses against M. tuberculosis. Recent studies have demonstrated that M. tuberculosis targets the DC-specific C-type lectin DC-SIGN to inhibit the immuno-stimulatory function of DC through the interaction of the mycobacterial mannosylated lipoarabinomannan (ManLAM) to DC-SIGN, which prevents DC maturation and induces the immuno-suppressive cytokine IL-10. This may contribute to survival and persistence of M. tuberculosis. Here, we have identified the specific pathogen-derived carbohydrate structure on ManLAM that is recognized by DC-SIGN. We have synthesized the mannose-cap oligosaccharides man-ara, (man)2-ara and (man)3-ara, and demonstrate that these neoglycoconjugates are specifically bound by DC-SIGN. Moreover, we demonstrate that the human and murine DC-SIGN homologue L-SIGN and SIGNR1, respectively, also interact with mycobacteria through ManLAM. Both homologues have the highest affinity for the (man)3-ara structure, similar to DC-SIGN. This study provides information about the specific carbohydrate structures on pathogens that are recognized by DC-SIGN, and may provide strategies to develop vaccines against these pathogens. Moreover, the identification of SIGNR1 as a receptor for ManLAM will enable in vivo studies to investigate the role of DC-SIGN in M. tuberculosis pathogenesis.
Department of Molecular Cell Biology & Immunology, VU University Medical Center, Amsterdam, The Netherlands.
Estella A
EA
Koppel
Irene S
IS
Ludwig
Marta Sanchez
MS
Hernandez
Todd L
TL
Lowary
Rajendrakumar R
RR
Gadikota
Alexander B
AB
Tuzikov
Christina M J E
CM
Vandenbroucke-Grauls
Yvette
Y
van Kooyk
Ben J
BJ
Appelmelk
Teunis B H
TB
Geijtenbeek
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002240:Carbohydrate Sequence; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology; D006801:Humans; D037181:Lectins, C-Type / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D037241:Mannose-Binding Lectins / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000378:metabolism; D009844:Oligosaccharides / Q000737:chemistry; D010957:Plasmids; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism; D014162:Transfection; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D008024:Ligands; D037241:Mannose-Binding Lectins; D009844:Oligosaccharides; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C433029:CLEC4M protein, human