硫酸化糖胺聚糖是白色念珠菌毒素念珠菌素的宿主上皮细胞靶标

IF 20.5 1区生物学 Q1 MICROBIOLOGY

Nature Microbiology Pub Date : 2024-09-16 DOI:10.1038/s41564-024-01794-8

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

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引用次数: 0

摘要

念珠菌素是真菌病原体白色念珠菌产生的一种细胞溶解肽，是一种关键的毒力因子。然而，其宿主细胞靶标仍然难以捉摸。在这里，我们在 TR146 人类口腔上皮细胞系中进行了全基因组功能缺失 CRISPR 筛选，发现糖胺聚糖（GAG）生物合成中的基因（XYLT2、B3GALT6 和 B3GAT3）被破坏后，对念珠菌素和活白念珠菌诱导的损伤具有抵抗力。表面等离子共振以及原子力和电子显微镜表明，念珠菌素能与硫酸化的 GAG 结合，从而促进其在宿主细胞表面的富集。添加外源硫酸化凝胶体或硫酸葡聚糖类似物可保护细胞免受念珠菌素引起的损伤。葡聚糖硫酸盐还能抑制白念珠菌的侵袭和真菌诱导的上皮细胞细胞因子的产生。在患有外阴阴道念珠菌病的小鼠中，局部使用硫酸葡聚糖可减少阴道内组织损伤和炎症。总之，硫酸化的凝胶体是念珠菌素的上皮细胞靶标，可用于治疗，保护细胞免受念珠菌素诱导的损伤。

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Sulfated glycosaminoglycans are host epithelial cell targets of the Candida albicans toxin candidalysin

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Sulfated glycosaminoglycans are host epithelial cell targets of the Candida albicans toxin candidalysin

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. Sulfated glycosaminoglycans are host cell targets of candidalysin, a cytolytic toxin of the fungal pathogen Candida albicans.

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来源期刊

Nature Microbiology Immunology and Microbiology-Microbiology

CiteScore

44.40

自引率

1.10%

发文量

226

期刊介绍： Nature Microbiology aims to cover a comprehensive range of topics related to microorganisms. This includes: Evolution: The journal is interested in exploring the evolutionary aspects of microorganisms. This may include research on their genetic diversity, adaptation, and speciation over time. Physiology and cell biology: Nature Microbiology seeks to understand the functions and characteristics of microorganisms at the cellular and physiological levels. This may involve studying their metabolism, growth patterns, and cellular processes. Interactions: The journal focuses on the interactions microorganisms have with each other, as well as their interactions with hosts or the environment. This encompasses investigations into microbial communities, symbiotic relationships, and microbial responses to different environments. Societal significance: Nature Microbiology recognizes the societal impact of microorganisms and welcomes studies that explore their practical applications. This may include research on microbial diseases, biotechnology, or environmental remediation. In summary, Nature Microbiology is interested in research related to the evolution, physiology and cell biology of microorganisms, their interactions, and their societal relevance.