The epithelium-produced growth factor midkine has fungicidal properties

Abstract

Objectives: The skin encounters many potential pathogens present in the environment, where Candida spp. are among the most common causes of fungal infestation. Midkine (MK) is a heparin-binding growth factor that is constitutively produced in the epidermis and this study looks at the antifungal activity of MK, potential co-localization and mode of action of MK. Methods and results: We show that MK is expressed in association with fungal infections of the skin. In vitro, MK showed strong fungicidal activity against Candida albicans and Candida parapsilosis. Scanning electron microscopy of fungi revealed blebbing and leakage of intracellular contents, indicating membrane interactions. Immunoelectron microscopy showed accumulation of MK in association with the membrane, but also a high degree of internalization, suggesting intracellular targets as well. Using liposome models mimicking fungal and human cell membranes (i.e. ergosterol- and cholesterol-containing membranes, respectively), MK was found to disrupt ergosterol-containing membranes to a higher degree than cholesterol-containing vesicles. Addition of increasing concentrations of salt caused a partial and dose-dependent decrease in the fungicidal activity exerted by MK in parallel with a decreased affinity for the yeast. However, at salt concentrations similar to those of an epithelial context (i.e. 50-100 mM), MK retained most of its fungicidal activity, in contrast to that of plasma (150 mM). Conclusions: The findings suggest that MK plays a role in host defence against fungal infections and could serve as a template for development of novel antifungal treatments. © The Author 2012. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.