白念珠菌“White-Gray-Opaque”三稳态转换系统的调控机制研究

Phenotypic variation is one of the most important biological traits of human pathogen Candida albicans. The ability of C. albicans to switch between different phenotypes is critical for its successful colonization and infections. White-opaque switching, which is a well-known bistable phenotypic switching system, has been reported to play a crucial role in sexual reproduction and virulence. Recently, we report a novel phenotype of C. albicans, referred as the gray phenotype, which is distinct from the white and opaque phenotypes in a number of aspects, including mating competency and virulence. The gray cell type, together with the white and opaque phenotypes forms a tristable phenotypic switching system. To date, the regulatory network controlling white-opaque bistable switching system are well-understood, but the molecular mechanisms of the tristable phenotypic switching system, especially in the case of the gray phenotype formation, are not clear. In this study, we will focus on exploring the molecular bases of the tristable phenotype switching system and its role in host adaptation and infection. A number of genetic approaches and high-throughput techniques including RNA-Seq, ChIP-Seq and library screening will be used. This project will benefit our understanding of the mechanisms of the evolution of virulence traits as well as pathogen-host interation relationship. Importantly, our research will also provide clues to study infection mechanisms in other pathogenic fungi.

形态的多样性是白念珠菌最重要的生物学特征之一。该菌应对宿主体内环境变化的能力和致病能力与形态转换密切相关。White-opaque转换在白念珠菌毒力和有性生殖等方面起重要作用，是形态转换研究的经典课题。而我们最近发现了该菌的一种新的形态-gray形态。Gray细胞与white和opaque细胞在交配能力、致病性等方面有明显区别，三者能够形成一种可逆且可遗传的三稳态转换系统。但目前对该系统的分子调控机制，尤其是gray细胞形成机制的研究还非常粗浅。本项目将在前期工作的基础上，利用RNA-Seq、ChIP-Seq及生化和遗传学等手段，弄清gray细胞形成及维持的分子基础，揭示三稳态系统的调控机制并绘制调控网络。明确不同形态细胞在宿主体内的共生和感染特性。本研究将阐明三稳态转换系统在白念珠菌毒性进化和感染中的作用，进一步认清该病原菌与宿主之间的互作机制，也将为其他病原真菌的感染机制研究提供启示。

以念珠菌为主的真菌感染已成为临床上越来越严重的问题。每年由念珠菌感染引发的死亡人数约为40万，且有数千万妇女、儿童和免疫缺陷患者遭受念珠菌浅部感染的困扰。已证实白念珠菌的致病性与形态多样性和可塑性密切相关。本项目着眼于念珠菌感染的临床实际需求，系统地探索白念珠菌形态转换重要调控基因和信号途径，揭示宿主环境因子影响形态转换和致病性的作用机制，发掘抗念珠菌新手段。本研究已取得了多项系统性强，影响力突出的研究成果。（1）发现了一系列调控白念珠菌形态转换的关键转录因子。（2）揭示细胞铜离子浓度直接影响gray形态的建成。（3）阐明三稳态形态转换系统在不同念珠菌物种中的普遍性。（4）揭示重要宿主环境因子CO2对白念珠菌形态转换的调控模式。（5）揭示宿主营养缺乏和氧化压力环境促进白念珠菌毒性进化机理。（6）报道中国首例“超级真菌”感染病例，发现硫酸铜具有重要的抗真菌功能，为遏制“超级真菌”感染提供了新策略。项目执行期间，项目负责人在PLoS Biology、PLoS Genetics等SCI杂志发表文章3篇，其中一篇入选Faculty of 1000（评级为very good）。

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