title: N-glycolylated peptidoglycan contributes to the immunogenicity but not pathogenicity of Mycobacterium tuberculosis.
abstract: Mycobacteria produce an unusual, glycolylated form of muramyl dipeptide (MDP) that is more potent and efficacious at inducing NOD2-mediated host responses. We tested the importance of this modified form of MDP in Mycobacterium tuberculosis by disrupting the gene, namH, responsible for this modification. In vitro, the namH mutant did not produce N-glycolylated muropeptides, but there was no alteration in colony morphology, growth kinetics, cellular morphology, or mycolic acid profile. Ex vivo, the namH mutant survived and replicated normally in murine and human macrophages, yet induced diminished production of tumor necrosis factor α. In vivo, namH disruption did not affect the bacterial burden during infection of C57BL/6 mice or cellular recruitment to the lungs but modestly prolonged survival after infection in Rag1(-/-) mice. These results indicate that the modified MDP is an important contributor to the unusual immunogenicity of mycobacteria but has a limited role in the pathogenesis of M. tuberculosis infection.
authors.affiliation: Department of Medicine, Research Institute of the McGill University Health Center, Montreal, Canada.
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Hansen
authors.forename: Solmaz A
authors.initials: SA
authors.lastname: Golchin
authors.forename: Frédéric J
authors.initials: FJ
authors.lastname: Veyrier
authors.forename: Pilar
authors.initials: P
authors.lastname: Domenech
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Boneca
authors.forename: Abul K
authors.initials: AK
authors.lastname: Azad
authors.forename: Murugesan V S
authors.initials: MV
authors.lastname: Rajaram
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
authors.forename: Maziar
authors.initials: M
authors.lastname: Divangahi
authors.forename: Michael B
authors.initials: MB
authors.lastname: Reed
authors.forename: Marcel A
authors.initials: MA
authors.lastname: Behr
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D058491:Bacterial Load; D002478:Cells, Cultured; D004195:Disease Models, Animal; D017353:Gene Deletion; D006801:Humans; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000201:enzymology / Q000276:immunology* / Q000472:pathogenicity*; D010457:Peptidoglycan / Q000737:chemistry / Q000276:immunology*; D011499:Protein Processing, Post-Translational; D016019:Survival Analysis; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology; D014774:Virulence
chemical_list: D010457:Peptidoglycan; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D006899:Mixed Function Oxygenases
keywords: N-acetyl muramic acid hydroxylase, NamH; N-glycolyl MDP; NOD2; tuberculosis