CWI信号途径对白念珠菌White-Opaque表型转换及致病性调控的机制

White-Opaque switching is an important strategy for Candida albicans to adapt to host environment, and causes a variety of changes of biological characteristics. Cell wall integrity(CWI) signaling pathway is a canonical pathway for remolding and remaining the integrity of fungal cell wall. Rlm1 in CWI pathway is a key factor for regulating genes associated with components and functions of fungal cell wall. We discovered in our previous study that knocking out RLM1 gene could cause a weakened competence for White-Opaque switching in Candida albicans, indicating that Rlm1 might be involved in the regulating of this kind of switching. However, the mechanism of the regulation is unclear. Does Rlm1 have an impact on the regulators of White-Opaque switching? How does CWI pathway cause the differences of the components of cell wall, virulence, interactions with host, and anti-fungal drug susceptibility between White cells and Opaque cells? We aim to investigate these questions on a molecular, cellular, and animal level, and so that provide new insights for understanding the regulation and significance of White-Opaque switching in Candida albicans.

White-Opaque表型转换是白念珠菌适应宿主环境的重要策略，引起多项生物学特性的改变。细胞壁完整性（CWI）信号途径是介导真菌细胞壁重构和维持其完整性的经典通路，通过转录因子Rlm1调控下游与细胞壁成分和功能相关的基因的表达。我们在前期研究中首次发现，敲除RLM1基因后白念珠菌的White-Opaque转换能力减弱，提示转录因子Rlm1参与了White-Opaque转换的调控。但具体机制尚不明确：CWI信号途径如何影响White-Opaque转换的调控，如何引起White表型与Opaque表型之间细胞壁构成的差异，两种表型的毒性、与宿主相互作用、对抗真菌药物敏感性是否具有差异。我们拟在分子、细胞和动物水平揭示CWI信号途径对白念珠菌White-Opaque转换的调控作用及对不同表型细胞壁构成和功能的影响，为了解白念珠菌White-Opaque表型转换的调控和生物学作用提供新的思路。

White-Opaque表型转换是白念珠菌适应宿主环境的重要策略，引起多项生物学特性的改变。细胞壁完整性（CWI）信号途径是介导真菌细胞壁重构和维持其完整性的经典通路，通过转录因子Rlm1调控下游与细胞壁成分和功能相关的基因的表达。我们在前期研究中首次发现，敲除RLM1基因后白念珠菌的White-Opaque转换能力减弱，提示转录因子Rlm1参与了White-Opaque转换的调控。但具体机制尚不明确：CWI信号途径如何影响White-Opaque转换的调控，如何引起White表型与Opaque表型之间细胞壁构成的差异，两种表型的毒性、与宿主相互作用、对抗真菌药物敏感性是否具有差异。我们在分子、细胞水平检测了CWI信号途径对白念珠菌White-Opaque转换的调控作用及对不同表型毒力和功能的影响。结果发现Glc作为碳源时，与野生型菌株相比，RLM1基因敲除菌株的White-Opaque转换率下降。RLM1基因敲除后，Opaque细胞的BRG1和CZF1基因表达降低。野生型菌株Opaque细胞RLM1、ROM2表达较低；White细胞RLM1、ROM2表达较高。RLM1敲除后Opaque细胞对卡泊芬净敏感性增强。以上结果提示RLM1对Opaque细胞形态的维持具有正向调节作用，能够降低Opaque细胞对卡泊芬净的敏感性，但RLM1对于CZF1基因的作用还有待进一步确认。