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中抗真菌药物耐药性的增加令人担忧。因此，有一个 需要新的抗真菌药物和治疗剂。C.白色念珠菌在细胞中起着关键作用， 壁生物发生、宿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 针对细胞壁蛋白质的药物。in C. DFG5和DCW1基因编码GPI锚定的糖苷酶 它们被定位在细胞壁上。DFG5和DCW1基因的同时缺失在C. 表明它们对生存至关重要。我们在C.白色念珠菌表明 由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在生物膜形成中具有关键作用，并调节Hog1 MAPK （促分裂原活化蛋白激酶）水平。此外，我们最近的初步数据显示， 表明Dfg5和Dcw1可能调节几丁质合成/重塑，几丁质是重要细胞壁完整性 决定簇，通过HOG MAPK途径。然而，Dfg5和Dcw1细胞壁蛋白在毒力和 致病性C.白色念珠菌尚未确定。因此，本提案的目的是确定 DFG5和DCW1在致病性和致病性中的功能。 具体地说，该项目旨在确定DFG5和DCW1在1）通过Hog1 MAPK的毒力中的作用 信号通路和2）口腔念珠菌病小鼠模型中的体内发病机制。靶向Dfg5和Dcw1， 它们的功能将导致新的和有效的抗真菌药物。

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.