title: The facultative intracellular pathogen Candida glabrata subverts macrophage cytokine production and phagolysosome maturation.
abstract: Although Candida glabrata is an important human pathogenic yeast, its pathogenicity mechanisms are largely unknown. Immune evasion strategies seem to play key roles during infection, since very little inflammation is observed in mouse models. Furthermore, C. glabrata multiplies intracellularly after engulfment by macrophages. In this study, we sought to identify the strategies that enable C. glabrata to survive phagosome biogenesis and antimicrobial activities within human monocyte-derived macrophages. We show that, despite significant intracellular proliferation, macrophage damage or apoptosis was not apparent, and production of reactive oxygen species was inhibited. Additionally, with the exception of GM-CSF, levels of pro- and anti-inflammatory cytokines were only marginally increased. We demonstrate that adhesion to and internalization by macrophages occur within minutes, and recruitment of endosomal early endosomal Ag 1 and lysosomal-associated membrane protein 1 indicates phagosome maturation. However, phagosomes containing viable C. glabrata, but not heat-killed yeasts, failed to recruit cathepsin D and were only weakly acidified. This inhibition of acidification did not require fungal viability, but it had a heat-sensitive surface attribute. Therefore, C. glabrata modifies the phagosome into a nonacidified environment and multiplies until the host cells finally lyse and release the fungi. Our results suggest persistence of C. glabrata within macrophages as a possible immune evasion strategy.
authors.affiliation: Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, 07745 Jena, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Seider
authors.forename: Sascha
authors.initials: S
authors.lastname: Brunke
authors.forename: Lydia
authors.initials: L
authors.lastname: Schild
authors.forename: Nadja
authors.initials: N
authors.lastname: Jablonowski
authors.forename: Duncan
authors.initials: D
authors.lastname: Wilson
authors.forename: Olivia
authors.initials: O
authors.lastname: Majer
authors.forename: Dagmar
authors.initials: D
authors.lastname: Barz
authors.forename: Albert
authors.initials: A
authors.lastname: Haas
authors.forename: Karl
authors.initials: K
authors.lastname: Kuchler
authors.forename: Martin
authors.initials: M
authors.lastname: Schaller
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hube
mesh_terms: D017209:Apoptosis / Q000276:immunology; D041221:Candida glabrata / Q000276:immunology* / Q000472:pathogenicity*; D002177:Candidiasis / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000382:microbiology*; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D020411:Oligonucleotide Array Sequence Analysis; D010588:Phagosomes / Q000276:immunology / Q000382:microbiology*; D016133:Polymerase Chain Reaction
chemical_list: D016207:Cytokines