title: Lipoarabinomannan mannose caps do not affect mycobacterial virulence or the induction of protective immunity in experimental animal models of infection and have minimal impact on in vitro inflammatory responses.
abstract: Mannose-capped lipoarabinomannan (ManLAM) is considered an important virulence factor of Mycobacterium tuberculosis. However, while mannose caps have been reported to be responsible for various immunosuppressive activities of ManLAM observed in vitro, there is conflicting evidence about their contribution to mycobacterial virulence in vivo. Therefore, we used Mycobacterium bovis BCG and M. tuberculosis mutants that lack the mannose cap of LAM to assess the role of ManLAM in the interaction of mycobacteria with the host cells, to evaluate vaccine-induced protection and to determine its importance in M. tuberculosis virulence. Deletion of the mannose cap did not affect BCG survival and replication in macrophages, although the capless mutant induced a somewhat higher production of TNF. In dendritic cells, the capless mutant was able to induce the upregulation of co-stimulatory molecules and the only difference we detected was the secretion of slightly higher amounts of IL-10 as compared to the wild type strain. In mice, capless BCG survived equally well and induced an immune response similar to the parental strain. Furthermore, the efficacy of vaccination against a M. tuberculosis challenge in low-dose aerosol infection models in mice and guinea pigs was not affected by the absence of the mannose caps in the BCG. Finally, the lack of the mannose cap in M. tuberculosis did not affect its virulence in mice nor its interaction with macrophages in vitro. Thus, these results do not support a major role for the mannose caps of LAM in determining mycobacterial virulence and immunogenicity in vivo in experimental animal models of infection, possibly because of redundancy of function.
authors.affiliation: Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Afonso-Barroso
authors.forename: Simon O
authors.initials: SO
authors.lastname: Clark
authors.forename: Ann
authors.initials: A
authors.lastname: Williams
authors.forename: Gustavo T
authors.initials: GT
authors.lastname: Rosa
authors.forename: Cláudia
authors.initials: C
authors.lastname: Nóbrega
authors.forename: Sandro
authors.initials: S
authors.lastname: Silva-Gomes
authors.forename: Sílvia
authors.initials: S
authors.lastname: Vale-Costa
authors.forename: Roy
authors.initials: R
authors.lastname: Ummels
authors.forename: Neil
authors.initials: N
authors.lastname: Stoker
authors.forename: Farahnaz
authors.initials: F
authors.lastname: Movahedzadeh
authors.forename: Peter
authors.initials: P
authors.lastname: van der Ley
authors.forename: Arjen
authors.initials: A
authors.lastname: Sloots
authors.forename: Marlène
authors.initials: M
authors.lastname: Cot
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Appelmelk
authors.forename: Germain
authors.initials: G
authors.lastname: Puzo
authors.forename: Jérôme
authors.initials: J
authors.lastname: Nigou
authors.forename: Jeroen
authors.initials: J
authors.lastname: Geurtsen
authors.forename: Rui
authors.initials: R
authors.lastname: Appelberg
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology; D004195:Disease Models, Animal; D006168:Guinea Pigs; D054884:Host-Pathogen Interactions; D008070:Lipopolysaccharides / Q000032:analysis*; D008264:Macrophages / Q000382:microbiology; D008358:Mannose / Q000032:analysis*; D051379:Mice; D050296:Microbial Viability; D009163:Mycobacterium bovis / Q000737:chemistry / Q000235:genetics / Q000254:growth & development / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000235:genetics / Q000254:growth & development / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D037521:Virulence Factors / Q000032:analysis
chemical_list: D008070:Lipopolysaccharides; D037521:Virulence Factors; C050016:lipoarabinomannan; D008358:Mannose