磷酸转运蛋白Pho84调控白念珠菌共生-致病转化的分子机制研究

As an opportunistic human fungal pathogen in clinic, Candida albicans can harmlessly exist in the mucous membrane of human gastrointestinal tract as a commensal on one hand and transit into a pathogen which causes severe candidiasis disease when immune system and microbiome are compromised on the other hand. Currently the molecular mechanisms contributing to the commensal-pathogen transition are still unclear. We previously identified the phosphate transporter Pho84 as a key regulator in C. albicans virulence. And our preliminary in vivo data show that Pho84 promotes gut commensalism of C. albicans. This fully indicates a critical role of Pho84 in C. albicans commensal-pathogen transition. In this project, we will investigate the role of Pho84 in regulating commensal-pathogen transition with two specific aims: 1) Mechanism of the protein expression, localization and gene expression profiling of Pho84 and the corresponding host regulators during the transition; (2) The molecular mechanism of Pho84 in regulating interaction between C. albicans and gut commensal bacteria. These results not only provide new insights into the molecular basis of commensal-pathogen transition, but also strengthen the understanding of the interaction among host, Candida albicans and gut microbiota. This will promote the development of new antifungal targets for treatment of candidiasis disease.

作为临床常见机会性致病真菌，白念珠菌可以共生于肠道等粘膜表面而不致病，但在机体免疫力低下或肠道菌群失调时可由共生菌转化为致病菌引发严重的念珠菌病，目前白念珠菌共生-致病转化的分子机制尚未阐明。我们前期研究发现磷酸转运蛋白Pho84对白念珠菌致病至关重要，近期体内结果表明Pho84促进白念珠菌肠道共生，充分说明Pho84很可能在调控共生-致病转化方面起关键作用。为探索Pho84调控白念珠菌共生-致病转化这一重要病理过程的分子机制，本项目将利用RNAseq、相互作用组学、蛋白组学、CRISPR-Cas9等技术探究共生-致病转化过程中：1）Pho84的蛋白表达、定位、基因表达调控及相应的宿主应答机制；2）Pho84调控宿主肠道内白念珠菌与其它菌群相互作用的分子机理。该研究将揭示白念珠菌共生-致病转化的新机制，增强对“宿主-白念珠菌-肠道菌群”三者互作的认识，为控制和预防真菌感染提供新作用靶点。

作为临床常见机会性致病真菌，白念珠菌可以共生于肠道等粘膜表面而不致病，但在机体免疫力低下或肠道菌群失调时可由共生菌转化为致病菌引发严重的念珠菌病，目前白念珠菌共生-致病转化的分子机制尚未阐明。本研究揭示了磷转运蛋白Pho84在白念珠菌肠道共生过程中的双调控新机制，即同时通过磷转运吸收和TORC1途径激活下游Try4转录因子的表达，进而上调共生和粘附相关基因的表达，最终促进白念珠菌肠道共生，且该机制是共生特异而非致病所需，值得一提的是，Pho84是真菌特异的，在人体中没有同源蛋白，因此可以作为抗真菌药物的潜在靶点。因此，本项目的完成阐明了白念珠菌这一常见人体机会性致病真菌在共生-致病转化中的特异分子途径和信号通路，为目前真菌微生物组如何感应外界营养长期定植于宿主肠道提供了新的研究线索，也为新型抗真菌药物的研发提供了新靶点。