title: The presence of a galactosamine substituent on the arabinogalactan of Mycobacterium tuberculosis abrogates full maturation of human peripheral blood monocyte-derived dendritic cells and increases secretion of IL-10.
abstract: Slow-growing and pathogenic Mycobacterium spp. are characterized by the presence of galactosamine (GalN) that modifies the interior branched arabinosyl residues of the arabinogalactan (AG) that is a major heteropolysaccharide cell wall component. The availability of null mutants of the polyprenyl-phospho-N-acetylgalactosaminyl synthase (Rv3631, PpgS) and the (N-acetyl-) galactosaminyl transferase (Rv3779) of Mycobacterium tuberculosis (Mtb) has provided a means to elucidate the role of the GalN substituent of AG in terms of host-pathogen interactions. Comparisons of treating human peripheral blood monocyte-derived dendritic cells (hPMC-DCs) with wild-type, Rv3631 and Rv3779 mutant strains of Mtb revealed increased expression of DC maturation markers, decreased affinity for a soluble DC-SIGN probe, reduced IL-10 secretion and increased TLR-2-mediated NF-κB activation among GalN-deficient Mtb strains compared to GalN-producing strains. Analysis of surface expression of a panel of defined or putative DC-SIGN ligands on both WT strains or either Rv3631 or Rv3779 mutant did not show significant differences suggesting that the role of the GalN substituent of AG may be to modulate access of the bacilli to immunologically-relevant receptor domains on DCs or contribute to higher ordered pathogen associated molecular pattern (PAMP)/pattern recognition receptor (PRR) interactions rather than the GalN-AG components having a direct immunological effect per se.
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1682, USA. Electronic address: william.wheat@colostate.edu.
authors.forename: William H
authors.initials: WH
authors.lastname: Wheat
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1682, USA.
authors.forename: Rabeb
authors.initials: R
authors.lastname: Dhouib
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1682, USA.
authors.forename: Shiva K
authors.initials: SK
authors.lastname: Angala
authors.affiliation: CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Département Mécanismes Moléculaires des Infections Mycobactériennes, 205 route de Narbonne, F-31077 Toulouse, France; Université de Toulouse, UPS, IPBS, F-31077 Toulouse, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Larrouy-Maumus
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1682, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Dobos
authors.affiliation: CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), Département Mécanismes Moléculaires des Infections Mycobactériennes, 205 route de Narbonne, F-31077 Toulouse, France; Université de Toulouse, UPS, IPBS, F-31077 Toulouse, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Nigou
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1682, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Spencer
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1682, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Jackson
mesh_terms: D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D005685:Galactans / Q000276:immunology* / Q000378:metabolism; D005688:Galactosamine / Q000276:immunology* / Q000378:metabolism; D005838:Genotype; D054884:Host-Pathogen Interactions; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000254:growth & development / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D005685:Galactans; C508609:IL10 protein, human; D016328:NF-kappa B; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D016753:Interleukin-10; D005688:Galactosamine; D017350:N-Acetylgalactosaminyltransferases; C005653:arabinogalactan
keywords: Arabinogalactan; Cell wall; DC-SIGN; Dendritic cell; GalN; GalN-AG; Galactosamine; Host response; Human PBMC; IL-10; Innate immunity; Mycobacterium; Mycobacterium tuberculosis; PAMP; PRR