title: The mannose cap of mycobacterial lipoarabinomannan does not dominate the Mycobacterium-host interaction.
abstract: Pathogenic mycobacteria have the ability to persist in phagocytic cells and to suppress the immune system. The glycolipid lipoarabinomannan (LAM), in particular its mannose cap, has been shown to inhibit phagolysosome fusion and to induce immunosuppressive IL-10 production via interaction with the mannose receptor or DC-SIGN. Hence, the current paradigm is that the mannose cap of LAM is a crucial factor in mycobacterial virulence. However, the above studies were performed with purified LAM, never with live bacteria. Here we evaluate the biological properties of capless mutants of Mycobacterium marinum and M. bovis BCG, made by inactivating homologues of Rv1635c. We show that its gene product is an undecaprenyl phosphomannose-dependent mannosyltransferase. Compared with parent strain, capless M. marinum induced slightly less uptake by and slightly more phagolysosome fusion in infected macrophages but this did not lead to decreased survival of the bacteria in vitro, nor in vivo in zebra fish. Loss of caps in M. bovis BCG resulted in a sometimes decreased binding to human dendritic cells or DC-SIGN-transfected Raji cells, but no differences in IL-10 induction were observed. In mice, capless M. bovis BCG did not survive less well in lung, spleen or liver and induced a similar cytokine profile. Our data contradict the current paradigm and demonstrate that mannose-capped LAM does not dominate the Mycobacterium-host interaction.
authors: Department of Medical Microbiology and Infection Control, VU University Medical Center, 1081 BT Amsterdam, The Netherlands. bj.appelmelk@vumc.nl
authors: B J
authors: BJ
authors: Appelmelk
authors: J
authors: J
authors: den Dunnen
authors: N N
authors: NN
authors: Driessen
authors: R
authors: R
authors: Ummels
authors: M
authors: M
authors: Pak
authors: J
authors: J
authors: Nigou
authors: G
authors: G
authors: Larrouy-Maumus
authors: S S
authors: SS
authors: Gurcha
authors: F
authors: F
authors: Movahedzadeh
authors: J
authors: J
authors: Geurtsen
authors: E J
authors: EJ
authors: Brown
authors: M M
authors: MM
authors: Eysink Smeets
authors: G S
authors: GS
authors: Besra
authors: P T J
authors: PT
authors: Willemsen
authors: T L
authors: TL
authors: Lowary
authors: Y
authors: Y
authors: van Kooyk
authors: J J
authors: JJ
authors: Maaskant
authors: N G
authors: NG
authors: Stoker
authors: P
authors: P
authors: van der Ley
authors: G
authors: G
authors: Puzo
authors: C M J E
authors: CM
authors: Vandenbroucke-Grauls
authors: C W
authors: CW
authors: Wieland
authors: T
authors: T
authors: van der Poll
authors: T B H
authors: TB
authors: Geijtenbeek
authors: A M
authors: AM
authors: van der Sar
authors: W
authors: W
authors: Bitter
mesh_terms: D000818:Animals; D016667:Bacterial Capsules / Q000378:metabolism / Q000502:physiology*; D004251:DNA Transposable Elements / Q000235:genetics; D003713:Dendritic Cells / Q000378:metabolism / Q000382:microbiology; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005816:Genetic Complementation Test; D054884:Host-Pathogen Interactions; D006801:Humans; D015151:Immunoblotting; D016753:Interleukin-10 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D008358:Mannose / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D008364:Mannosyltransferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008958:Models, Molecular; D016254:Mutagenesis, Insertional; D009154:Mutation; D009161:Mycobacterium / Q000378:metabolism / Q000502:physiology*; D009164:Mycobacterium Infections / Q000378:metabolism / Q000382:microbiology; D015027:Zebrafish
chemical_list: D004251:DNA Transposable Elements; D008070:Lipopolysaccharides; C050016:lipoarabinomannan; D016753:Interleukin-10; D008364:Mannosyltransferases; D008358:Mannose