Zinc Binding Inhibits Cellular Uptake and Antifungal Activity of Histatin-5 in Candida albicans .

Journal Article (Journal Article)

Histatin-5 (Hist-5) is a polycationic, histidine-rich antimicrobial peptide with potent antifungal activity against the opportunistic fungal pathogen Candida albicans . Hist-5 can bind metals in vitro, and metals have been shown to alter the fungicidal activity of the peptide. Previous reports on the effect of Zn2+ on Hist-5 activity have been varied and seemingly contradictory. Here, we present data elucidating the dynamic role Zn2+ plays as an inhibitory switch to regulate Hist-5 fungicidal activity. A novel fluorescently labeled Hist-5 peptide (Hist-5*) was developed to visualize changes in internalization and localization of the peptide as a function of metal availability in the growth medium. Hist-5* was verified for use as a model peptide and retained antifungal activity and mode of action similar to native Hist-5. Cellular growth assays showed that Zn2+ had a concentration-dependent inhibitory effect on Hist-5 antifungal activity. Imaging by confocal microscopy revealed that equimolar concentrations of Zn2+ kept the peptide localized along the cell periphery rather than internalizing, thus preventing cytotoxicity and membrane disruption. However, the Zn-induced decrease in Hist-5 activity and uptake was rescued by decreasing the Zn2+ availability upon addition of a metal chelator EDTA or S100A12, a Zn-binding protein involved in the innate immune response. These results lead us to suggest a model wherein commensal C. albicans may exist in harmony with Hist-5 at concentrations of Zn2+ that inhibit peptide internalization and antifungal activity. Activation of host immune processes that initiate Zn-sequestering mechanisms of nutritional immunity could trigger Hist-5 internalization and cell killing.

Full Text

Duke Authors

Cited Authors

  • Campbell, JX; Gao, S; Anand, KS; Franz, KJ

Published Date

  • September 2022

Published In

Volume / Issue

  • 8 / 9

Start / End Page

  • 1920 - 1934

PubMed ID

  • 35997625

Pubmed Central ID

  • PMC9671271

Electronic International Standard Serial Number (EISSN)

  • 2373-8227

International Standard Serial Number (ISSN)

  • 2373-8227

Digital Object Identifier (DOI)

  • 10.1021/acsinfecdis.2c00289

Language

  • eng