Candida albicans glycosidases, Dfg5 and Dcw1, in virulence and pathogenesis

大多数粘膜和侵袭性真菌感染是由口腔真菌病原体念珠菌引起的 白色念珠菌。念珠菌属物种的抗真菌药物耐药性呈惊人上升趋势。结果，有一个 需要新型抗真菌药物和治疗方法。白色念珠菌的细胞壁蛋白在细胞中发挥着关键作用 壁生物发生、宿主入侵和疾病发病机制。但目前尚无已知的抗真菌药物 靶向细胞壁蛋白的药物。在白色念珠菌中，DFG5 和 DCW1 基因编码 GPI 锚定糖苷酶 是针对细胞壁的。同时删除 DFG5 和 DCW1 基因对于 C. 白色念珠菌表明它们对于生存至关重要。我们发表的关于白色念珠菌的研究结果表明 DFG5 和 DCW1 编码的酶参与细胞壁蛋白与细胞壁基质的交联。 数据还表明 DFG5 和 DCW1 在生物膜形成和调节 Hog1 MAPK 中具有关键作用 基础条件下的（丝裂原激活蛋白激酶）水平。此外，我们最近的初步数据 表明 Dfg5 和 Dcw1 可能调节几丁质合成/重塑，这是重要的细胞壁完整性 决定因素，通过 HOG MAPK 途径。然而，Dfg5 和 Dcw1 细胞壁蛋白在毒力和 白色念珠菌的发病机制尚未确定。因此，本提案的目标是确定 DFG5 和 DCW1 在这种重要的人类真菌病原体的毒力和发病机制中的功能。 具体来说，该项目旨在通过 Hog1 MAPK 确定 DFG5 和 DCW1 在 1) 毒力中的作用 信号通路和2）口腔念珠菌病小鼠模型的体内发病机制。以 Dfg5 和 DCw1 为目标， 它们的功能将导致新型有效的抗真菌药物的产生。

A majority of mucosal and invasive fungal infections are caused by the oral fungal pathogen, Candida albicans. There is an alarming rise in antifungal drug resistance among Candida species. As a result, there is a need for novel antifungal drugs and therapeutics. The cell wall proteins in C. albicans play critical roles in cell wall biogenesis, host invasion and disease pathogenesis. However, currently there are no known antifungal drugs that target cell wall proteins. In C. albicans, DFG5 and DCW1 genes encode GPI-anchored glycosidases that are targeted to the cell wall. The simultaneous deletion of the DFG5 and DCW1 genes is lethal in C. albicans indicating that they are critical for survival. Our published findings in C. albicans indicate that the enzymes encoded by DFG5 and DCW1 are involved in cell wall protein cross-linking to the cell wall matrix. Data also show that DFG5 and DCW1 have a pivotal role in biofilm formation and regulate Hog1 MAPK (mitogen activated protein kinase) levels under basal conditions. Additionally, our recent preliminary data indicate that Dfg5 and Dcw1 may regulate chitin synthesis/remodeling, an important cell wall integrity determinant, via HOG MAPK pathway. However, the role of Dfg5 and Dcw1 cell wall proteins in virulence and pathogenesis of C. albicans is yet to be determined. Therefore, the objective of this proposal is to determine the functions of DFG5 and DCW1 in virulence and pathogenesis, in this important human fungal pathogen. Specifically, the project aims to determine the roles of DFG5 and DCW1 in 1) virulence via Hog1 MAPK signaling pathway and 2) in vivo pathogenesis in a mouse model of oral candidiasis. Targeting Dfg5 and Dcw1, and their functions will lead to novel and efficacious antifungal drugs.