Details

Autor(en) / Beteiligte

• Hein, Kyaw Zaw
• Takahashi, Hitoshi
• Tsumori, Toshiko
• Yasui, Yukihiko
• Nanjoh, Yasuko
• Toga, Tetsuo
• Wu, Zhihong
• Grötzinger, Joachim
• Jung, Sascha
• Wehkamp, Jan
• Schroeder, Bjoern O.
• Schroeder, Jens M.
• Morita, Eishin

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2015-10, Vol.112 (42), p.13039-13044

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2015

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• The unexpected resistance of psoriasis lesions to fungal infections suggests local production of an antifungal factor. We purifiedTrichophyton 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 moldAspergillus fumigatus, but notCandida albicans. Antifungal activity was inhibited by Zn2+, 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 Zn2+-chelator. Immunogold electron microscopy studies revealed that it penetrates fungal cells, implicating possible intracellular actions. In support with our hypothesis, the cell-penetrating Zn2+-chelator TPEN was found to function as a broad-spectrum antifungal. Ultrastructural analyses of redS100A7-treatedT. rubrumrevealed 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 bothT. rubrumandA. 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 mouseAspergillusinfection model for lung infection and found antifungal activity in both in vivo animal systems. Thus, selective fungal cell-penetrating Zn2+-chelators could be useful as an urgently needed novel antifungal therapeutic, which induces programmed cell death in numerous fungi.