N-乙酰葡糖胺感知因子Ngs1介导的信号途径调控白念珠菌形态发生和致病性的分子机制

Candida albicans is the most prevalent fungal pathogen of humans. In susceptible patients, commensal C. albicans can enter the bloodstream and cause a frequently fatal disseminated infection. The mortality of systemic infection is over 50%. C. albicans utilizes N-acetylglucosamine (GlcNAc) as the major carbon source in the host microenvironments. GlcNAc can also promote C. albicans cells to undergo hyphal development and phenotypic switching between white and opaque heritable cell states, which are linked to its virulence, infection of distinct host niches and immune evasion. However, the mechanism how GlcNAc induces these morphogenesis programs remains largely unknown. We have identified Ngs1 as GlcNAc sensor, which plays critical roles on the regulation of GlcNAc-induced morphogenesis programs in C. albicans. In this proposal, we will uncover the mechanism how Ngs1 transduces GlcNAc signals to induce morphological transitions, which promote the pathogenicity of C. albicans. Our study will elucidate how fungal pathogens infect tissues in response to nutrients offered by host niches. As Ngs1-mediated signaling pathways do not exist in mammalian and bacteria, the anti-fungal drugs targeting to Ngs1 will be less toxicity to humans and their microbiota. This study will help to explore new drugs.

白念珠菌是最常见的人体机会性致病真菌，当免疫力下降时，共生状态的白念珠菌会侵染人体造成系统性感染，致死率超过50%。N-乙酰葡糖胺是白念珠菌在宿主微环境中主要碳源营养，可诱导白念珠菌的菌丝发育及白灰转换。由于致病真菌的形态发生与致病性密切相关，因此N-乙酰葡糖胺作为信号分子调控白念珠菌毒性发挥的作用开始被关注，但分子机制尚不清楚。我们前期的工作鉴定出N-乙酰葡糖胺感知因子Ngs1，并发现Ngs1调控白念珠菌菌丝发育和白灰转换。本项目将通过遗传与生化手段以及功能基因组学的研究揭示N-乙酰葡糖胺通过与感受器Ngs1的结合传递信号，诱导形态转换促进致病性发挥的分子机制，进而阐明致病真菌如何通过应答宿主体内营养物质来实现组织侵染。Ngs1介导的信号途径在哺乳动物以及细菌中均不存在，以此为靶标可以减少对人体及正常菌群的伤害，本研究将为抗真菌药的研发提供新思路。