title: A peptide derived from the highly conserved protein GAPDH is involved in tissue protection by different antifungal strategies and epithelial immunomodulation.
abstract: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has an important role not only in glycolysis but also in nonmetabolic processes, including transcription activation and apoptosis. We report the isolation of a human GAPDH (hGAPDH) (2-32) fragment peptide from human placental tissue exhibiting antimicrobial activity. The peptide was internalized by cells of the pathogenic yeast Candida albicans and initiated a rapid apoptotic mechanism, leading to killing of the fungus. Killing was dose-dependent, with 10 μg ml (3.1 μM) and 100 μg ml hGAPDH (2-32) depolarizing 45% and 90% of the fungal cells in a population, respectively. Experimental C. albicans infection induced epithelial hGAPDH (2-32) expression. Addition of the peptide significantly reduced the tissue damage as compared with untreated experimental infection. Secreted aspartic proteinase (Sap) activity of C. albicans was inhibited by the fragment at higher concentrations, with a median effective dose of 160 mg l(-1) (50 μM) for Sap1p and 200 mg l(-1) (63 μM) for Sap2p, whereas Sap3 was not inhibited at all. Interestingly, hGAPDH (2-32) induced significant epithelial IL-8 and GM-CSF secretion and stimulated Toll-like receptor 4 expression at low concentrations independently of the presence of C. albicans, without any toxic mucosal effects. In the future, the combination of different antifungal strategies, e.g., a conventional fungicidal with immunomodulatory effects and the inhibition of fungal virulence factors, might be a promising treatment option.
authors: Department of Dermatology, Eberhard Karls University Tübingen, Tübingen, Germany.
authors: Jeanette
authors: J
authors: Wagener
authors: Josef J
authors: JJ
authors: Schneider
authors: Susann
authors: S
authors: Baxmann
authors: Hubert
authors: H
authors: Kalbacher
authors: Claudia
authors: C
authors: Borelli
authors: Sabine
authors: S
authors: Nuding
authors: Robert
authors: R
authors: Küchler
authors: Jan
authors: J
authors: Wehkamp
authors: Matthias D
authors: MD
authors: Kaeser
authors: Daniela
authors: D
authors: Mailänder-Sanchez
authors: Christina
authors: C
authors: Braunsdorf
authors: Bernhard
authors: B
authors: Hube
authors: Lydia
authors: L
authors: Schild
authors: Wolf-Georg
authors: WG
authors: Forssmann
authors: Hans-Christian
authors: HC
authors: Korting
authors: Cornelia
authors: C
authors: Liepke
authors: Martin
authors: M
authors: Schaller
mesh_terms: D000935:Antifungal Agents / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D057055:Aspartic Acid Proteases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002176:Candida albicans / Q000187:drug effects / Q000378:metabolism; D002177:Candidiasis / Q000188:drug therapy / Q000276:immunology; D002460:Cell Line; D004848:Epithelium / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D005260:Female; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000096:biosynthesis / Q000737:chemistry*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D016209:Interleukin-8 / Q000096:biosynthesis / Q000276:immunology; D009061:Mouth Mucosa / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D010446:Peptide Fragments / Q000302:isolation & purification / Q000494:pharmacology*; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000276:immunology
chemical_list: D000935:Antifungal Agents; C508606:CXCL8 protein, human; D016209:Interleukin-8; D010446:Peptide Fragments; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D057055:Aspartic Acid Proteases