TY - JOUR
T1 - Identification of the mycobacterial carbohydrate structure that binds the C-type lectins DC-SIGN, L-SIGN and SIGNR1
AU - Koppel, Estella A
AU - Ludwig, Irene S
AU - Hernandez, Marta Sanchez
AU - Lowary, Todd L
AU - Gadikota, Rajendrakumar R
AU - Tuzikov, Alexander B
AU - Vandenbroucke-Grauls, Christina M J E
AU - van Kooyk, Yvette
AU - Appelmelk, Ben J
AU - Geijtenbeek, Teunis B H
PY - 2004
Y1 - 2004
N2 - 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.
AB - 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.
KW - Animals
KW - Antigens, CD/chemistry
KW - Binding Sites
KW - Carbohydrate Sequence
KW - Cell Adhesion Molecules/chemistry
KW - Dendritic Cells/immunology
KW - Humans
KW - Lectins, C-Type/chemistry
KW - Ligands
KW - Mannose-Binding Lectins/chemistry
KW - Mice
KW - Molecular Sequence Data
KW - Mycobacterium tuberculosis/chemistry
KW - Oligosaccharides/chemistry
KW - Plasmids
KW - Receptors, Cell Surface/chemistry
KW - Transfection
M3 - Article
C2 - 15481146
VL - 209
SP - 117
EP - 127
JO - Immunobiology
JF - Immunobiology
SN - 0171-2985
IS - 1-2
ER -