Identification of the mycobacterial carbohydrate structure that binds the C-type lectins DC-SIGN, L-SIGN and SIGNR1

Estella A. Koppel; Irene S. Ludwig; Marta Sanchez Hernandez; Todd L. Lowary; Rajendrakumar R. Gadikota; Alexander B. Tuzikov; Christina M. J. E. Vandenbroucke-Grauls; Yvette van Kooyk; Ben J. Appelmelk; Teunis B. H. Geijtenbeek

doi:https://doi.org/10.1016/j.imbio.2004.03.003

Identification of the mycobacterial carbohydrate structure that binds the C-type lectins DC-SIGN, L-SIGN and SIGNR1

Estella A. Koppel, Irene S. Ludwig, Marta Sanchez Hernandez, Todd L. Lowary, Rajendrakumar R. Gadikota, Alexander B. Tuzikov, Christina M. J. E. Vandenbroucke-Grauls, Yvette van Kooyk, Ben J. Appelmelk, Teunis B. H. Geijtenbeek

Research output: Contribution to journal › Article › Academic › peer-review

78 Citations (Scopus)

Abstract

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

Original language	English
Pages (from-to)	117-127
Number of pages	11
Journal	Immunobiology
Volume	209
Issue number	1-2
DOIs	https://doi.org/10.1016/j.imbio.2004.03.003
Publication status	Published - 2004

Keywords

Animals
Antigens, CD/chemistry
Binding Sites
Carbohydrate Sequence
Cell Adhesion Molecules/chemistry
Dendritic Cells/immunology
Humans
Lectins, C-Type/chemistry
Ligands
Mannose-Binding Lectins/chemistry
Mice
Molecular Sequence Data
Mycobacterium tuberculosis/chemistry
Oligosaccharides/chemistry
Plasmids
Receptors, Cell Surface/chemistry
Transfection

Access to Document

https://doi.org/10.1016/j.imbio.2004.03.003

Cite this

Koppel, E. A., Ludwig, I. S., Hernandez, M. S., Lowary, T. L., Gadikota, R. R., Tuzikov, A. B., Vandenbroucke-Grauls, C. M. J. E., van Kooyk, Y., Appelmelk, B. J., & Geijtenbeek, T. B. H. (2004). Identification of the mycobacterial carbohydrate structure that binds the C-type lectins DC-SIGN, L-SIGN and SIGNR1. Immunobiology, 209(1-2), 117-127. https://doi.org/10.1016/j.imbio.2004.03.003

@article{066867c2b32d4280b3aa206f4ec03b89,

title = "Identification of the mycobacterial carbohydrate structure that binds the C-type lectins DC-SIGN, L-SIGN and SIGNR1",

abstract = "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",

keywords = "Animals, Antigens, CD/chemistry, Binding Sites, Carbohydrate Sequence, Cell Adhesion Molecules/chemistry, Dendritic Cells/immunology, Humans, Lectins, C-Type/chemistry, Ligands, Mannose-Binding Lectins/chemistry, Mice, Molecular Sequence Data, Mycobacterium tuberculosis/chemistry, Oligosaccharides/chemistry, Plasmids, Receptors, Cell Surface/chemistry, Transfection",

author = "Koppel, {Estella A.} and Ludwig, {Irene S.} and Hernandez, {Marta Sanchez} and Lowary, {Todd L.} and Gadikota, {Rajendrakumar R.} and Tuzikov, {Alexander B.} and Vandenbroucke-Grauls, {Christina M. J. E.} and {van Kooyk}, Yvette and Appelmelk, {Ben J.} and Geijtenbeek, {Teunis B. H.}",

year = "2004",

doi = "https://doi.org/10.1016/j.imbio.2004.03.003",

language = "English",

volume = "209",

pages = "117--127",

journal = "Immunobiology",

issn = "0171-2985",

publisher = "Urban und Fischer Verlag GmbH und Co. KG",

number = "1-2",

}

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

U2 - https://doi.org/10.1016/j.imbio.2004.03.003

DO - https://doi.org/10.1016/j.imbio.2004.03.003

M3 - Article

C2 - 15481146

SN - 0171-2985

VL - 209

SP - 117

EP - 127

JO - Immunobiology

JF - Immunobiology

IS - 1-2

ER -