Identification of mycobacterial alpha-glucan as a novel ligand for DC-SIGN: involvement of mycobacterial capsular polysaccharides in host immune modulation.
Mycobacterium tuberculosis possesses a variety of immunomodulatory factors that influence the host immune response. When the bacillus encounters its target cell, the outermost components of its cell envelope are the first to interact. Mycobacteria, including M. tuberculosis, are surrounded by a loosely attached capsule that is mainly composed of proteins and polysaccharides. Although the chemical composition of the capsule is relatively well studied, its biological function is only poorly understood. The aim of this study was to further assess the functional role of the mycobacterial capsule by identifying host receptors that recognize its constituents. We focused on alpha-glucan, which is the dominant capsular polysaccharide. Here we demonstrate that M. tuberculosis alpha-glucan is a novel ligand for the C-type lectin DC-SIGN (dendritic cell-specific ICAM-3-grabbing nonintegrin). By using related glycogen structures, we show that recognition of alpha-glucans by DC-SIGN is a general feature and that the interaction is mediated by internal glucosyl residues. As for mannose-capped lipoarabinomannan, an abundant mycobacterial cell wall-associated glycolipid, binding of alpha-glucan to DC-SIGN stimulated the production of immunosuppressive IL-10 by LPS-activated monocyte-derived dendritic cells. By using specific inhibitors, we show that this IL-10 induction was DC-SIGN-dependent and also required acetylation of NF-kappaB. Finally, we demonstrate that purified M. tuberculosis alpha-glucan, in contrast to what has been reported for fungal alpha-glucan, was unable to activate TLR2.
Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands. jeroen.geurtsen@vumc.nl
Jeroen
J
Geurtsen
Sunita
S
Chedammi
Joram
J
Mesters
Marlène
M
Cot
Nicole N
NN
Driessen
Tounkang
T
Sambou
Ryo
R
Kakutani
Roy
R
Ummels
Janneke
J
Maaskant
Hiroki
H
Takata
Otto
O
Baba
Tatsuo
T
Terashima
Nicolai
N
Bovin
Christina M J E
CM
Vandenbroucke-Grauls
Jérôme
J
Nigou
Germain
G
Puzo
Anne
A
Lemassu
Mamadou
M
Daffé
Ben J
BJ
Appelmelk
D016667:Bacterial Capsules / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D005936:Glucans / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D005936:Glucans; D016753:Interleukin-10; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C495342:TLR2 protein, human; C050016:lipoarabinomannan