title: Pathogenic fungi regulate immunity by inducing neutrophilic myeloid-derived suppressor cells.
abstract: Despite continuous contact with fungi, immunocompetent individuals rarely develop pro-inflammatory antifungal immune responses. The underlying tolerogenic mechanisms are incompletely understood. Using both mouse models and human patients, we show that infection with the human pathogenic fungi Aspergillus fumigatus and Candida albicans induces a distinct subset of neutrophilic myeloid-derived suppressor cells (MDSCs), which functionally suppress T and NK cell responses. Mechanistically, pathogenic fungi induce neutrophilic MDSCs through the pattern recognition receptor Dectin-1 and its downstream adaptor protein CARD9. Fungal MDSC induction is further dependent on pathways downstream of Dectin-1 signaling, notably reactive oxygen species (ROS) generation as well as caspase-8 activity and interleukin-1 (IL-1) production. Additionally, exogenous IL-1β induces MDSCs to comparable levels observed during C. albicans infection. Adoptive transfer and survival experiments show that MDSCs are protective during invasive C. albicans infection, but not A. fumigatus infection. These studies define an innate immune mechanism by which pathogenic fungi regulate host defense.
authors.affiliation: Department of Pediatrics I, University of Tübingen, 72076 Tübingen, Germany. Electronic address: nikolaus.rieber@med.uni-tuebingen.de.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rieber
authors.affiliation: Department of Pediatrics I, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Anurag
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Pediatrics I, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Hasan
authors.initials: H
authors.lastname: Öz
authors.affiliation: Department of Pediatrics I, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Carevic
authors.affiliation: Department of Medicine II, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Bouzani
authors.affiliation: IZKF Research Group for Experimental Stem Cell Transplantation, Department of Medicine II, 97080 Würzburg, Germany.
authors.forename: Jorge
authors.initials: J
authors.lastname: Amich
authors.affiliation: Department of Pediatrics I, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ost
authors.affiliation: Department of Pediatrics I, University of Tübingen, 72076 Tübingen, Germany; Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Pediatrics I, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Marlene
authors.initials: M
authors.lastname: Ballbach
authors.affiliation: Department of Pediatrics I, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Schäfer
authors.affiliation: Department of Pediatrics I, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Mezger
authors.affiliation: Institute of Cell Biology, Department of Immunology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Sascha N
authors.initials: SN
authors.lastname: Klimosch
authors.affiliation: Institute of Cell Biology, Department of Immunology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Alexander N R
authors.initials: AN
authors.lastname: Weber
authors.affiliation: Department of Pediatrics I, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.affiliation: Microbiology Institute - Clinical Microbiology, Immunology and Hygiene, University Hospital of Erlangen and Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Krappmann
authors.affiliation: Department of Pediatrics, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Liese
authors.affiliation: Department of Neurology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Maik
authors.initials: M
authors.lastname: Engeholm
authors.affiliation: Department of Neurology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.affiliation: Department of Oncology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Helmut Rainer
authors.initials: HR
authors.lastname: Salih
authors.affiliation: Department of Infectious and Pediatric Immunology, Medical and Health Science Center, University of Debrecen, 4032 Debrecen, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Marodi
authors.affiliation: Centre of Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Speckmann
authors.affiliation: Centre of Chronic Immunodeficiency (CCI), University Medical Center Freiburg and University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.affiliation: Aberdeen Fungal Group, Section of Immunology and Infection, University of Aberdeen, AB24 3FX Aberdeen, UK.
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Brown
authors.affiliation: IZKF Research Group for Experimental Stem Cell Transplantation, Department of Medicine II, 97080 Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beilhack
authors.affiliation: Department of Medicine II, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Loeffler
authors.affiliation: Department of Pediatrics I, University of Tübingen, 72076 Tübingen, Germany. Electronic address: dominik.hartl@med.uni-tuebingen.de.
authors.forename: Dominik
authors.initials: D
authors.lastname: Hartl
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000276:immunology / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000276:immunology*; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D002176:Candida albicans / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology / Q000382:microbiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions; D006801:Humans; D007108:Immune Tolerance; D037181:Lectins, C-Type / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000276:immunology*; D015398:Signal Transduction; D000099181:Dectin-1
chemical_list: D053468:CARD Signaling Adaptor Proteins; D037181:Lectins, C-Type; D000099181:Dectin-1; C505855:CARD9 protein, human; C513280:Card9 protein, mouse