title: Mannan core branching of lipo(arabino)mannan is required for mycobacterial virulence in the context of innate immunity.
abstract: The causative agent of tuberculosis (TB), Mycobacterium tuberculosis, remains an important worldwide health threat. Although TB is one of the oldest infectious diseases of man, a detailed understanding of the mycobacterial mechanisms underlying pathogenesis remains elusive. Here, we studied the role of the α(1→2) mannosyltransferase MptC in mycobacterial virulence, using the Mycobacterium marinum zebrafish infection model. Like its M. tuberculosis orthologue, disruption of M. marinum mptC (mmar_3225) results in defective elongation of mannose caps of lipoarabinomannan (LAM) and absence of α(1→2)mannose branches on the lipomannan (LM) and LAM mannan core, as determined by biochemical analysis (NMR and GC-MS) and immunoblotting. We found that the M. marinum mptC mutant is strongly attenuated in embryonic zebrafish, which rely solely on innate immunity, whereas minor virulence defects were observed in adult zebrafish. Strikingly, complementation with the Mycobacterium smegmatis mptC orthologue, which restored mannan core branching but not cap elongation, was sufficient to fully complement the virulence defect of the mptC mutant in embryos. Altogether our data demonstrate that not LAM capping, but mannan core branching of LM/LAM plays an important role in mycobacterial pathogenesis in the context of innate immunity.
authors.affiliation: Department of Medical Microbiology and Infection Control, VU University Medical Center, van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands.
authors.forename: Esther J M
authors.initials: EJ
authors.lastname: Stoop
authors.forename: Arun K
authors.initials: AK
authors.lastname: Mishra
authors.forename: Nicole N
authors.initials: NN
authors.lastname: Driessen
authors.forename: Gunny
authors.initials: G
authors.lastname: van Stempvoort
authors.forename: Pascale
authors.initials: P
authors.lastname: Bouchier
authors.forename: Theo
authors.initials: T
authors.lastname: Verboom
authors.forename: Lisanne M
authors.initials: LM
authors.lastname: van Leeuwen
authors.forename: Marion
authors.initials: M
authors.lastname: Sparrius
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Raadsen
authors.forename: Maaike
authors.initials: M
authors.lastname: van Zon
authors.forename: Nicole N
authors.initials: NN
authors.lastname: van der Wel
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Jeroen
authors.initials: J
authors.lastname: Geurtsen
authors.forename: Wilbert
authors.initials: W
authors.lastname: Bitter
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Appelmelk
authors.forename: Astrid M
authors.initials: AM
authors.lastname: van der Sar
mesh_terms: D000818:Animals; D058491:Bacterial Load; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism*; D008358:Mannose / Q000737:chemistry; D009165:Mycobacterium Infections, Nontuberculous / Q000276:immunology; D019910:Mycobacterium marinum / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D020102:Mycobacterium smegmatis / Q000472:pathogenicity; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000472:pathogenicity; D010731:Phosphoenolpyruvate Sugar Phosphotransferase System / Q000235:genetics / Q000378:metabolism*; D014376:Tuberculosis / Q000276:immunology; D015027:Zebrafish / Q000276:immunology / Q000382:microbiology
chemical_list: D008070:Lipopolysaccharides; C050016:lipoarabinomannan; C064351:lipomannan; D010731:Phosphoenolpyruvate Sugar Phosphotransferase System; C037992:phosphoenolpyruvate-mannose phosphotransferase; D008358:Mannose
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