Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nat Chem Biol. 2022 Jul;18(7):762-773. doi: 10.1038/s41589-022-01035-1. Epub 2022 Jun 6.
Mucins are large gel-forming polymers inside the mucus barrier that inhibit the yeast-to-hyphal transition of Candida albicans, a key virulence trait of this important human fungal pathogen. However, the molecular motifs in mucins that inhibit filamentation remain unclear despite their potential for therapeutic interventions. Here, we determined that mucins display an abundance of virulence-attenuating molecules in the form of mucin O-glycans. We isolated and cataloged >100 mucin O-glycans from three major mucosal surfaces and established that they suppress filamentation and related phenotypes relevant to infection, including surface adhesion, biofilm formation and cross-kingdom competition between C. albicans and the bacterium Pseudomonas aeruginosa. Using synthetic O-glycans, we identified three structures (core 1, core 1 + fucose and core 2 + galactose) that are sufficient to inhibit filamentation with potency comparable to the complex O-glycan pool. Overall, this work identifies mucin O-glycans as host molecules with untapped therapeutic potential to manage fungal pathogens.
黏蛋白是黏液屏障中的大型凝胶形成聚合物，可抑制白色念珠菌（一种重要的人类真菌病原体）从酵母相到菌丝相的转变，这是其关键毒力特征。然而，尽管黏蛋白在治疗干预方面具有很大的潜力，但抑制丝状生长的黏蛋白分子结构仍不清楚。在这里，我们发现黏蛋白以黏蛋白 O-聚糖的形式显示出丰富的毒力减弱分子。我们从三个主要黏膜表面分离并编目了超过 100 种黏蛋白 O-聚糖，并证实它们可抑制丝状生长和与感染相关的相关表型，包括表面黏附、生物膜形成以及白色念珠菌和细菌铜绿假单胞菌之间的跨界竞争。使用合成 O-聚糖，我们确定了三种结构（核心 1、核心 1+岩藻糖和核心 2+半乳糖），它们足以抑制丝状生长，其效力可与复杂的 O-聚糖库相媲美。总的来说，这项工作确定了黏蛋白 O-聚糖作为宿主分子，具有未开发的治疗潜力，可以用于管理真菌病原体。
