title: A critical role for lipophosphoglycan in proinflammatory responses of dendritic cells to Leishmania mexicana.
abstract: Recognition of pathogen-associated molecular patterns (PAMP) influences the response of dendritic cells (DC) and therefore development of innate and adaptive immunity. Different forms of Leishmania mexicana have distinct effects on DC, with promastigotes and amastigotes being activating and apparently neutral, respectively. We investigated whether stage-specific differences in surface composition might account for these distinct effects. Amastigotes and promastigotes lacking the lpg1 gene needed for lipophosphoglycan (LPG) biosynthesis could not activate DC in vitro. Genome-wide transcriptional profiling of DC infected with wild-type or mutant promastigotes or wild-type amastigotes revealed that wild-type promastigotes induce an inflammatory signature that is lacking in DC exposed to the other parasite forms. The proinflammatory response pattern was partly recovered by reconstitution of lpg1 expression in lpg1-/- parasites, and exposure to purified LPG increased the expression of MHC class II and CD86 on DC. Infection with wild-type but not lpg1-/- promastigotes increased the number of activated DC in draining lymph nodes, and this was correlated with lower early parasite burdens in wild-type-infected animals. These in vivo and in vitro results suggest an LPG-dependent activation of DC that contributes to host defense and agree with the notion that the parasites evolved under immune pressure to down-regulate PAMP expression in mammalian hosts.
authors.affiliation: Max-Planck-Institute for Infection Biology, Department of Molecular Biology, Berlin, Germany.
authors.forename: Toni
authors.initials: T
authors.lastname: Aebischer
authors.forename: Clare L
authors.initials: CL
authors.lastname: Bennett
authors.forename: Mattia
authors.initials: M
authors.lastname: Pelizzola
authors.forename: Caterina
authors.initials: C
authors.lastname: Vizzardelli
authors.forename: Norman
authors.initials: N
authors.lastname: Pavelka
authors.forename: Matteo
authors.initials: M
authors.lastname: Urbano
authors.forename: Monica
authors.initials: M
authors.lastname: Capozzoli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Luchini
authors.forename: Thomas
authors.initials: T
authors.lastname: Ilg
authors.forename: Francesca
authors.initials: F
authors.lastname: Granucci
authors.forename: C Clare
authors.initials: CC
authors.lastname: Blackburn
authors.forename: Paola
authors.initials: P
authors.lastname: Ricciardi-Castagnoli
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005700:Galactosyltransferases / Q000378:metabolism; D020869:Gene Expression Profiling; D006028:Glycosphingolipids / Q000096:biosynthesis / Q000276:immunology*; D018664:Interleukin-12 / Q000378:metabolism; D053762:Interleukin-12 Subunit p40; D007894:Leishmania mexicana / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D051379:Mice; D021122:Protein Subunits / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism
chemical_list: D006028:Glycosphingolipids; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D015800:Protozoan Proteins; C008290:lipophosphonoglycan; D018664:Interleukin-12; D005700:Galactosyltransferases; C083281:LPG1 protein, Leishmania