title: The fungal quorum-sensing molecule farnesol activates innate immune cells but suppresses cellular adaptive immunity.
abstract: Farnesol, produced by the polymorphic fungus Candida albicans, is the first quorum-sensing molecule discovered in eukaryotes. Its main function is control of C. albicans filamentation, a process closely linked to pathogenesis. In this study, we analyzed the effects of farnesol on innate immune cells known to be important for fungal clearance and protective immunity. Farnesol enhanced the expression of activation markers on monocytes (CD86 and HLA-DR) and neutrophils (CD66b and CD11b) and promoted oxidative burst and the release of proinflammatory cytokines (tumor necrosis factor alpha [TNF-α] and macrophage inflammatory protein 1 alpha [MIP-1α]). However, this activation did not result in enhanced fungal uptake or killing. Furthermore, the differentiation of monocytes to immature dendritic cells (iDC) was significantly affected by farnesol. Several markers important for maturation and antigen presentation like CD1a, CD83, CD86, and CD80 were significantly reduced in the presence of farnesol. Furthermore, farnesol modulated migrational behavior and cytokine release and impaired the ability of DC to induce T cell proliferation. Of major importance was the absence of interleukin 12 (IL-12) induction in iDC generated in the presence of farnesol. Transcriptome analyses revealed a farnesol-induced shift in effector molecule expression and a down-regulation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor during monocytes to iDC differentiation. Taken together, our data unveil the ability of farnesol to act as a virulence factor of C. albicans by influencing innate immune cells to promote inflammation and mitigating the Th1 response, which is essential for fungal clearance.
  
  
  OBJECTIVE
  Farnesol is a quorum-sensing molecule which controls morphological plasticity of the pathogenic yeast Candida albicans. As such, it is a major mediator of intraspecies communication. Here, we investigated the impact of farnesol on human innate immune cells known to be important for fungal clearance and protective immunity. We show that farnesol is able to enhance inflammation by inducing activation of neutrophils and monocytes. At the same time, farnesol impairs differentiation of monocytes into immature dendritic cells (iDC) by modulating surface phenotype, cytokine release and migrational behavior. Consequently, iDC generated in the presence of farnesol are unable to induce proper T cell responses and fail to secrete Th1 promoting interleukin 12 (IL-12). As farnesol induced down-regulation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor, desensitization to GM-CSF could potentially explain transcriptional reprofiling of iDC effector molecules. Taken together, our data show that farnesol can also mediate Candida-host communication and is able to act as a virulence factor.
authors.affiliation: Septomics Research Centre, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Leonhardt
authors.affiliation: Septomics Research Centre, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany.
authors.forename: Steffi
authors.initials: S
authors.lastname: Spielberg
authors.affiliation: Septomics Research Centre, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Weber
authors.affiliation: BioControl GmbH, Jena, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Albrecht-Eckardt
authors.forename: Markus
authors.initials: M
authors.lastname: Bläss
authors.forename: Ralf
authors.initials: R
authors.lastname: Claus
authors.affiliation: University Hospital Jena, Institute of Transfusion Medicine, Jena, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Barz
authors.affiliation: Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Scherlach
authors.affiliation: Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hertweck
authors.affiliation: University Hospital Wuerzburg, Medical Clinic and Polyclinic II, Wuerzburg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Löffler
authors.affiliation: Septomics Research Centre, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hünniger
authors.affiliation: Septomics Research Centre, Friedrich Schiller University and Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany oliver.kurzai@hki-jena.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kurzai
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects*; D002176:Candida albicans / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005204:Farnesol / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D053038:Quorum Sensing; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D037521:Virulence Factors; D005204:Farnesol