不同形态的白色念珠菌与口腔上皮细胞相互作用的机制研究

Conditional pathogen Candida albicans caused mucosal infection is the most common fungal infectious disease in oral cavity. Oral mucosal infection becomes one of the leading diseases which are hazardous to health and increase the economic burden as the ever-growing immunocompromised population. The interaction between C. albicans and oral epithelial cells is the key to understanding the mucosal pathogenesis of C. albicans. However, the interactions between C. albicans with different forms and oral epithelial cells, the regulation of oral epithelial cells on C. albicans morphology etc, are not clear. Even worse, treating C. albicans is challenge due to the lack of effective antifungal drugs and the drug resistance. In this study, we will investigate the interactions between C. albicans and oral epithelial cells systematically by using dual RNA-Seq, including the yeast form (Commensalism), the pseudohyphal form (Transformation) and the haphal form (Pathogenesis). The extracellular vesicles secreted by C. albicans hyphae will be also proved as a new model during the mucosal pathogenesis in this study. The “fungal-host” interactions will lead to the discovery of new class of antifungal compounds which can block the interactions but not inhibit the fungi to avoid the drug resistance and drug toxicity.

条件性致病真菌白色念珠菌导致的黏膜感染是口腔中最常见的真菌感染性疾病。随着免疫缺陷等人群的增加，口腔黏膜感染成为危害健康、增加经济负担的重要疾病。白色念珠菌与口腔上皮细胞的相互作用是认识白色念珠菌黏膜感染致病机制的关键环节。然而不同形态的白色念珠菌与口腔上皮细胞相互作用及其差异，口腔上皮细胞调控白色念珠菌形态发育等方面的机制尚不清楚。而且临床新型抗真菌药物缺乏，耐药性严重，毒副作用大。针对以上问题，本项目采用互作转录组学为核心，全面系统地研究不同形态发育阶段的白色念珠菌与口腔上皮细胞相互作用，解析酵母形态白色念珠菌的共生机制，假菌丝形态白色念珠菌的转化机制，菌丝形态白色念珠菌的致病机制，并基于首次发现的白色念珠菌可分泌“胞外囊泡”损伤上皮细胞的结果为基础，研究白色念珠菌黏膜感染中的新机制。同时基于相互作用机制，筛选阻断二者相互作用的新型抗真菌活性物质，为研发真菌感染治疗药物提供新的策略。

条件性致病真菌白色念珠菌导致的黏膜感染是口腔中最常见的真菌感染性疾病，随着免疫缺陷等人群的增加，口腔黏膜感染成为危害健康、增加经济负担的重要疾病。白色念珠菌与口腔上皮细胞的相互作用是认识白色念珠菌黏膜感染的致病机制的关键环节。然而不同形态的白色念珠菌与口腔上皮细胞如何相互作用的机制尚不清楚。针对以上科学问题本项目系统地研究不同形态发育阶段的白色念珠菌与口腔上皮细胞相互作用，并基于首次发现的白色念珠菌可分泌“胞外囊泡”损伤上皮细胞的为基础，研究白色念珠菌黏膜感染中的新机制。同时，根据机制研究，筛选新型抗真菌活性物质。项目发现“CHK1-HOG1-线粒体能量代谢”是白色念珠菌与口腔上皮细胞作用的关键通路，双组分系统关键基因CHK1负调控MAPK激酶HOG1，HOG1通过转录因子SKO1与NDT80，分别负调控致病毒力因子，正调控免疫逃逸能力。同时HOG1通过影响线粒体功能，调节白色念珠菌能量代谢，通过EFG1来影响白色念珠菌菌丝发育。不同形态白色念珠菌还可分泌的胞外囊泡，均通过激活白色念珠菌“精氨酸-NO”途径，抑制ROS，促进白色念珠菌增殖与感染能力。且胞外囊泡可直接进入口腔上皮细胞，上调GSMD E，诱发口腔上皮细胞焦亡。最后通过筛选，发现青蒿素、阿维菌素、芦荟大黄素与活性肽可靶向白色念珠菌线粒体能量答谢，阻断其与口腔上皮细胞的作用，抑制白色念珠菌对口腔黏膜的感染。本项目研究研究结果，揭示了白色念珠菌口腔黏膜感染的机制，并为新型抗真菌药物的研发提供新的策略。