title: Inhibiting the immunoproteasome exacerbates the pathogenesis of systemic Candida albicans infection in mice.
abstract: Apart from its role in MHC class I antigen processing, the immunoproteasome has recently been implicated in the modulation of T helper cell differentiation under polarizing conditions in vitro and in the pathogenesis of autoimmune diseases in vivo. In this study, we investigated the influence of LMP7 on T helper cell differentiation in response to the fungus Candida albicans. We observed a strong effect of ONX 0914, an LMP7-selective inhibitor of the immunoproteasome, on IFN-γ and IL-17A production by murine splenocytes and human peripheral blood mononuclear cells (PBMCs) stimulated with C. albicans in vitro. Using a murine model of systemic candidiasis, we could confirm reduced generation of IFN-γ- and IL-17A-producing cells in ONX 0914 treated mice in vivo. Interestingly, ONX 0914 treatment resulted in increased susceptibility to systemic candidiasis, which manifested at very early stages of infection. Mice treated with ONX 0914 showed markedly increased kidney and brain fungal burden which resulted in enhanced neutrophil recruitment and immunopathology. Together, these results strongly suggest a role of the immunoproteasome in promoting proinflammatory T helper cells in response to C. albicans but also in affecting the innate antifungal immunity in a T helper cell-independent manner.
authors.affiliation: Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany.|Konstanz Research School Chemical Biology (KoRS-CB), University of Konstanz, Konstanz, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mundt
authors.affiliation: Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany.|Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Basler
authors.affiliation: Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany.|FlowKon Core Facility for Cell Sorting and Flow Cytometry, University of Konstanz, Konstanz, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Buerger
authors.affiliation: Institute of Medical Psychology and Behavioural Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Engler
authors.affiliation: Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany.|Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland.
authors.forename: Marcus
authors.initials: M
authors.lastname: Groettrup
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology / Q000401:mortality; D015169:Colony Count, Microbial; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D056747:Immunomodulation / Q000187:drug effects; D007668:Kidney; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D051379:Mice; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D016207:Cytokines; D009842:Oligopeptides; C542291:PR-957; D061988:Proteasome Inhibitors; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex