Institute for Infection and Immunity, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Pharmaceutical Sciences Program, College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.
Nat Microbiol. 2024 Oct;9(10):2553-2569. doi: 10.1038/s41564-024-01794-8. Epub 2024 Sep 16.
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.
白色念珠菌产生的细胞溶解肽——念珠菌溶素是一种关键的毒力因子，但宿主细胞靶点仍不清楚。本研究在 TR146 人口腔上皮细胞系中进行了全基因组功能丧失 CRISPR 筛选，鉴定出糖胺聚糖 (GAG) 生物合成基因（XYLT2、B3GALT6 和 B3GAT3）的缺失赋予了细胞对念珠菌溶素和活白色念珠菌诱导的损伤的抗性。表面等离子体共振、原子力和电子显微镜表明，念珠菌溶素结合硫酸化 GAG，促进其在宿主细胞表面的富集。添加外源性硫酸化 GAG 或类似物硫酸葡聚糖可保护细胞免受念珠菌溶素诱导的损伤。硫酸葡聚糖还抑制白色念珠菌侵袭和真菌诱导的上皮细胞细胞因子产生。在患有外阴阴道念珠菌病的小鼠中，局部给予硫酸葡聚糖可减少阴道组织损伤和炎症。综上所述，硫酸化 GAG 是念珠菌溶素的上皮细胞靶点，可用于治疗以保护细胞免受念珠菌溶素诱导的损伤。
