Sulfated Glycosaminoglycans Are Host Epithelial Cell Targets of the Candida Albicans Toxin Candidalysin

Overview

Journal Nat Microbiol

Specialties Microbiology
Parasitology

Date 2024 Sep 16

PMID 39285260

Authors

Jianfeng Lin

Jian Miao

Katherine G Schaefer

Charles M Russell

Robert J Pyron

Fuming Zhang

Quynh T Phan

Norma V Solis

Hong Liu

Masato Tashiro

Jonathan S Dordick

Robert J Linhardt

Michael R Yeaman

Gavin M King

Francisco N Barrera

Brian M Peters

Scott G Filler

Affiliations

Soon will be listed here.

Abstract

Candidalysin, a cytolytic peptide produced by the fungal pathogen Candida albicans, is a key virulence factor. However, its host cell targets remain elusive. Here we performed a genome-wide loss-of-function CRISPR screen in the TR146 human oral epithelial cell line and identified that disruption of genes (XYLT2, B3GALT6 and B3GAT3) in glycosaminoglycan (GAG) biosynthesis conferred resistance to damage induced by candidalysin and live C. albicans. Surface plasmon resonance and atomic force and electron microscopy indicated that candidalysin binds to sulfated GAGs, facilitating its enrichment on the host cell surface. Adding exogenous sulfated GAGs or the analogue dextran sulfate protected cells against candidalysin-induced damage. Dextran sulfate also inhibited C. albicans invasion and fungal-induced epithelial cell cytokine production. In mice with vulvovaginal candidiasis, topical dextran sulfate administration reduced intravaginal tissue damage and inflammation. Collectively, sulfated GAGs are epithelial cell targets of candidalysin and can be used therapeutically to protect cells from candidalysin-induced damage.

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