title: Disulphide-reduced psoriasin is a human apoptosis-inducing broad-spectrum fungicide.
abstract: The unexpected resistance of psoriasis lesions to fungal infections suggests local production of an antifungal factor. We purified Trichophyton rubrum-inhibiting activity from lesional psoriasis scale extracts and identified the Cys-reduced form of S100A7/psoriasin (redS100A7) as a principal antifungal factor. redS100A7 inhibits various filamentous fungi, including the mold Aspergillus fumigatus, but not Candida albicans. Antifungal activity was inhibited by Zn(2+), suggesting that redS100A7 interferes with fungal zinc homeostasis. Because S100A7-mutants lacking a single cysteine are no longer antifungals, we hypothesized that redS100A7 is acting as a Zn(2+)-chelator. Immunogold electron microscopy studies revealed that it penetrates fungal cells, implicating possible intracellular actions. In support with our hypothesis, the cell-penetrating Zn(2+)-chelator TPEN was found to function as a broad-spectrum antifungal. Ultrastructural analyses of redS100A7-treated T. rubrum revealed marked signs of apoptosis, suggesting that its mode of action is induction of programmed cell death. TUNEL, SYTOX-green analyses, and caspase-inhibition studies supported this for both T. rubrum and A. fumigatus. Whereas redS100A7 can be generated from oxidized S100A7 by action of thioredoxin or glutathione, elevated redS100A7 levels in fungal skin infection indicate induction of both S100A7 and its reducing agent in vivo. To investigate whether redS100A7 and TPEN are antifungals in vivo, we used a guinea pig tinea pedes model for fungal skin infections and a lethal mouse Aspergillus infection model for lung infection and found antifungal activity in both in vivo animal systems. Thus, selective fungal cell-penetrating Zn(2+)-chelators could be useful as an urgently needed novel antifungal therapeutic, which induces programmed cell death in numerous fungi.
authors.affiliation: Department of Dermatology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan;
authors.forename: Kyaw Zaw
authors.initials: KZ
authors.lastname: Hein
authors.affiliation: Department of Dermatology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan;
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Nursing, Faculty of Health and Welfare, Prefectural University of Hiroshima, Mihara 723-0053, Japan; Department of Anatomy and Morphological Neuroscience, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan;
authors.forename: Toshiko
authors.initials: T
authors.lastname: Tsumori
authors.affiliation: Department of Anatomy and Morphological Neuroscience, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan;
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Yasui
authors.affiliation: Research Center, Nihon Nohyaku Co., Ltd., Kawachi-Nagano, Osaka 586-0094, Japan;
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Nanjoh
authors.affiliation: Research Center, Nihon Nohyaku Co., Ltd., Kawachi-Nagano, Osaka 586-0094, Japan;
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Toga
authors.affiliation: Department of Dermatology, University-Hospital Schleswig-Holstein, 24105 Kiel, Germany;
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, 24098 Kiel, Germany;
authors.forename: Joachim
authors.initials: J
authors.lastname: Grötzinger
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, 24098 Kiel, Germany;
authors.forename: Sascha
authors.initials: S
authors.lastname: Jung
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, 70376 Stuttgart, Germany; Department of Internal Medicine 1, Robert-Bosch Hospital, 70376 Stuttgart, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Wehkamp
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, 70376 Stuttgart, Germany;
authors.forename: Bjoern O
authors.identifier: http://orcid.org/0000-0002-6716-8284
authors.initials: BO
authors.lastname: Schroeder
authors.affiliation: Department of Dermatology, University-Hospital Schleswig-Holstein, 24105 Kiel, Germany; jschroeder@dermatology.uni-kiel.de emorita@med.shimane-u.ac.jp.
authors.forename: Jens M
authors.initials: JM
authors.lastname: Schroeder
authors.affiliation: Department of Dermatology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; jschroeder@dermatology.uni-kiel.de emorita@med.shimane-u.ac.jp.
authors.forename: Eishin
authors.initials: E
authors.lastname: Morita
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001228:Aspergillosis / Q000188:drug therapy; D001232:Aspergillus fumigatus / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D004195:Disease Models, Animal; D004220:Disulfides / Q000737:chemistry*; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D010084:Oxidation-Reduction; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000935:Antifungal Agents; D004220:Disulfides; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human
keywords: S100A7; antifungal; epithelial defense; innate immunity; psoriasin