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 白念珠菌。在假丝酵母菌中，抗真菌药物耐药性的上升令人担忧。因此，有一个 需要新的抗真菌药物和治疗药物。白念珠菌的细胞壁蛋白在细胞中起着至关重要的作用。 壁生物发生、寄主入侵和疾病发病机制。然而，目前还没有已知的抗真菌药物 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 它们是针对细胞壁的。DFG5和DCW1基因同时缺失对华支睾吸虫是致命的。 白念珠菌表明它们对生存至关重要。我们发表的白念珠菌研究结果表明， DFG5和DCW1编码的酶参与了细胞壁蛋白与细胞壁基质的交联。 数据还表明，DFG5和DCW1在生物膜的形成中起着关键作用，并调节Hog1 MAPK (丝裂原活化蛋白激酶)在基础条件下的水平。另外，我们最近的初步数据 提示Dfg5和Dcw1可能调节几丁质的合成/重塑，这是一种重要的细胞壁完整性 决定簇，通过HOG MAPK途径。然而，Dfg5和Dcw1细胞壁蛋白在毒力和 白念珠菌的发病机制尚不清楚。因此，这项提案的目标是确定 在这种重要的人类真菌病原体中，DFG5和DCW1在毒力和致病机制中的作用。 具体地说，该项目旨在通过Hog1 MAPK确定DFG5和DCW1在毒力中的作用 信号途径和2)口腔念珠菌病小鼠模型的体内发病机制。目标是Dfg5和Dcw1， 它们的作用将导致新的有效的抗真菌药物。

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.