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Proc Natl Acad Sci U S A. 2015 Oct 20;112(42):13039-44. doi: 10.1073/pnas.1511197112. Epub 2015 Oct 5.

Disulphide-reduced psoriasin is a human apoptosis-inducing broad-spectrum fungicide.

Author information

1
Department of Dermatology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan;
2
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;
3
Department of Anatomy and Morphological Neuroscience, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan;
4
Research Center, Nihon Nohyaku Co., Ltd., Kawachi-Nagano, Osaka 586-0094, Japan;
5
Department of Dermatology, University-Hospital Schleswig-Holstein, 24105 Kiel, Germany;
6
Institute of Biochemistry, Christian-Albrechts-University, 24098 Kiel, Germany;
7
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.
8
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, 70376 Stuttgart, Germany;
9
Department of Dermatology, University-Hospital Schleswig-Holstein, 24105 Kiel, Germany; jschroeder@dermatology.uni-kiel.de emorita@med.shimane-u.ac.jp.
10
Department of Dermatology, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan; jschroeder@dermatology.uni-kiel.de emorita@med.shimane-u.ac.jp.

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.

KEYWORDS:

S100A7; antifungal; epithelial defense; innate immunity; psoriasin

PMID:
26438863
PMCID:
PMC4620902
DOI:
10.1073/pnas.1511197112
[Indexed for MEDLINE]
Free PMC Article

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