基于氨基葡萄糖应答的Crz1调控新型隐球菌毒力和形态转化的分子机制

新型隐球菌能在外界信号刺激下进行酵母菌丝之间转换，进而调控毒力大小。我们最近发现的氨基葡萄糖可以作为一个新的信号分子促进新型隐球菌从酵母向菌丝转换，这个过程必须依赖于调控蛋白Crz1。根据前人结果和我们已有数据，我们假设氨基葡萄糖能够影响新型隐球菌的毒力，并且Crz1在毒力调控方面起到核心作用。本项目拟通过动物感染实验证实氨基葡萄糖能够降低新型隐球菌的毒力，并且论证调控蛋白Crz1将会起到一个至关重要的作用。本项目将从分子机制阐述Crz1是如何调控新型隐球菌在氨基葡萄糖信号刺激下的毒力变化和形态转换，通过RNA-seq和Chip-seq来寻找被Crz1调控的下游靶标基因，着手研究新型隐球菌对于氨基葡萄糖应答的通路；最后，本项目从生物化学和蛋白质结构生物学的层面上解释Crz1调控靶标基因的分子机制。通过本研究有助于从新的方向来寻找新型隐球菌感染的预防疫苗和治疗药物。

Cryptococcus neoformans, a human fungal pathogen, can undergo bidirectional switch between the yeast and the hypha form in response to different intracellular and extracellular factors such as pheromone and dehydration. Morphotype is linked to virulence in Cryptococcus, with the filamentous form being avirulent like in many other environmental dimorphic fungal pathogens. Recently, we found that glucosamine (GlcN) could stimulate Cryptococcus to undergo yeast-to-hyphal morphotype switch. Excitingly, glucosamine enabled self-filamentation in serotype A isolates, including one of the most virulent clinical isolate and the most widely used reference strain H99. And this switch stimulated by GlcN is dependent on a transcriptional factor Crz1. However, it is not clear how Crz1 regulates the response of Cryptococcus neoformans to glucosamine. Also, it is not clear whether Crz1 is a virulent factor, which is involved into Cryptococcal virulence. In this proposal, we will figure out the pathway of response to glucosamine by investigating Crz1-regulated downstream targets. We will test the Cryptococcal virulence with or without Crz1 when treated with glucosamine and confirm whether the Crz1 plays a key role in the regulation of virulence.