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

白色念珠菌糖苷酶 Dfg5 和 Dcw1 的毒力和发病机制

基本信息

批准号：
9891314
负责人：
Abhiram Maddi
金额：
$ 15.95万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9891314
关键词：
Acquired Immunodeficiency Syndrome Affect Antifungal Agents Biogenesis C-terminal Cancer Patient Candida Candida albicans Candidiasis Cell Separation Cell Wall Cell membrane Cell physiology Centers for Disease Control and Prevention (U.S.)Chitin Chitin Synthase Clinical Data Defect Development Diagnosis Disease Disseminated candidiasis Drug Targeting Enzymes Event Family Funding Fungal Drug Resistance Future Gene Expression Genes Glycoside Hydrolases Goals Human Immunocompromised Host In Vitro Incidence Infant Investigation Knock-out Life MAP Kinase Gene Mannosyltransferases Microbial Biofilms Mitogen-Activated Protein Kinases Modeling Morphogenesis Mucous Membrane Mus Mutation Mycoses N-terminal Neurospora crassa Oral candidiasis Oral mucous membrane structure Pathogenesis Pathway interactions Patients Phagocytes Phenotype Play Prevalence Proteins Publishing Quantitative Reverse Transcriptase PCR Regulation Reporting Research Resistance Risk Role Saccharomyces cerevisiae Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Protein Testing Therapeutic Virulence conditional mutant crosslink drug development in vivo inhibitor/antagonist mouse model mutant new therapeutic target novel oral fungal overexpression pathogenic fungus recurrent infection response therapeutic target vaginal candidiasis

项目摘要

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.

大多数粘膜和侵入性真菌感染是由口腔真菌病原体，念珠菌引起的白色唱片。念珠菌物种之间的抗真菌药物抗药性令人震惊。结果，有一个需要新颖的抗真菌药物和治疗剂。白色念珠菌中的细胞壁蛋白在细胞中起关键作用壁生物发生，宿主入侵和疾病发病机理。但是，目前尚无已知抗真菌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锚定糖苷酶针对细胞壁的目标。 DFG5和DCW1基因的同时缺失在C中致命。白色唱片表明它们对于生存至关重要。我们在白色念珠菌中发表的发现表明由DFG5和DCW1编码的酶参与细胞壁蛋白交联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 （有丝分裂原激活的蛋白激酶）在基础条件下水平。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确定性，通过Hog Mapk途径。但是，DFG5和DCW1细胞壁蛋白在毒力和白色念珠菌的发病机理尚未确定。因此，该提议的目的是确定在这种重要的人类真菌病原体中，DFG5和DCW1在毒力和发病机理中的功能。具体而言，该项目旨在确定DFG5和DCW1在1）通过HOG1 MAPK毒力的作用信号通路和2）口服念珠菌病小鼠模型中的体内发病机理。针对DFG5和DCW1，它们的功能将导致新颖有效的抗真菌药物。