Regulation of morphogenesis in C. albicans

白色念珠菌形态发生的调控

基本信息

批准号：
9312992
负责人：
James B Konopka
金额：
$ 22.01万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-02-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9312992
关键词：
Affect Amphotericin Antifungal Agents Antifungal Therapy Antioxidants Azoles Candida albicans Cell Wall Cell membrane Cells Complex Copper Cytoplasmic Tail Defect Development Drug resistance Effectiveness Energy Metabolism Environment Extracellular Domain Flavodoxin Fluconazole Gene Proteins Goals Grant Growth High temperature of physical object Hospitals Human Impairment Individual Infection Integral Membrane Protein Lipid Peroxidation Lipid Peroxides Lipids Mammalian Cell Mediating Medical Membrane Membrane Proteins Microbial Biofilms Mitochondria Morphogenesis Mutagenesis Mutation Mycoses Nutrient Organ Organism Oxidative Stress Pathogenesis Pathogenicity Pathway interactions Peripheral Pharmaceutical Preparations Play Process Protein Family Proteins Quinone Reductases Regulation Resistance Role SERPINA4 gene Sepsis Stress Systemic infection Temperature Testing Therapeutic Therapeutic Intervention Time Tissues Transmembrane Domain Ubiquinone Virulence Virulence Factors aging population antimicrobial peptide extracellular fungus improved in vivo mutant new therapeutic target novel novel therapeutic intervention oxidation pathogen prevent resistant strain role model success uptake

项目摘要

Candida albicans is the most common cause of mucosal and systemic fungal infections in humans and is frequently responsible for hospital-acquired bloodstream infections. There is an urgent need to improve the therapeutic management of C. albicans infections, since current antifungal drugs have limited effectiveness and drug-resistant strains are emerging. The pathogenic effects of C. albicans are caused by its ability to grow in the host and disseminate to internal organs. Central to these processes is the plasma membrane, an essential barrier that mediates a broad range of functions that are critical for virulence. These functions include cell wall synthesis, secretion of virulence factors, morphogenesis, and nutrient uptake. The importance of the plasma membrane for virulence is underscored by the fact that it is directly or indirectly the target of the currently used antifungal drugs. Recent studies have revealed that the fungal plasma membrane is divided into distinct subdomains, including the punctate patches termed eisosomes. These 300 nm-sized domains contain integral membrane proteins, such as Sur7, and an adjacent complex of >20 peripheral membrane proteins including Pil1 and Lsp1 that promote formation of eisosomes. Our recent studies showed that Sur7, Pil1, and Lsp1 are the key players in the eisosome, as their mutation causes multiple defects including impaired cell wall synthesis, abnormal morphogenesis, and increased sensitivity to stress, oxidation, and antifungal drugs. Therefore, the Aims of our current proposal are to determine how eisosomes regulate three functions that are required for virulence: (Aim 1) cell wall synthesis and invasive hyphal morphogenesis, (Aim 2) resistance to different types of stress including copper and high temperature, and (Aim 3) a novel antioxidant pathway we discovered that protects the plasma membrane from oxidation and is needed for virulence. The proposed studies will identify novel drug targets and increase our understanding of the effects of current antifungal drugs. Defining eisosome function in C. albicans will also provide a model for the role of these plasma membrane domains in other pathogenic fungi.

白色念珠菌是人类粘膜和全身真菌感染的最常见原因并且经常导致医院获得性血流感染。迫切需要改善白色念珠菌感染的治疗管理，因为目前的抗真菌药物已效果有限且耐药菌株不断出现。白色念珠菌的致病作用是由于其在宿主体内生长并传播到内脏器官的能力引起的。这些的核心质膜是介导多种功能的重要屏障，对毒力至关重要。这些功能包括细胞壁合成、毒力因子的分泌、形态发生和营养吸收。质膜对于毒力的重要性是强调它是目前使用的抗真菌药物的直接或间接目标。最近的研究表明，真菌质膜分为不同的子域，包括称为 eisosomes 的点状斑块。这些 300 nm 大小的域包含积分膜蛋白，例如 Sur7，以及超过 20 个外周膜蛋白的相邻复合物包括促进 eisosome 形成的 Pil1 和 Lsp1。我们最近的研究表明 Sur7， Pil1 和 Lsp1 是 eisosome 中的关键角色，因为它们的突变会导致多种缺陷包括细胞壁合成受损、形态发生异常和对压力的敏感性增加，抗氧化、抗真菌药物。因此，我们当前提案的目标是确定如何 eisosomes 调节毒力所需的三种功能：（目标 1）细胞壁合成和侵入性菌丝形态发生，（目标 2）对不同类型的胁迫（包括铜和高温，以及（目标 3）我们发现的一种新的抗氧化途径，可以保护血浆膜免受氧化并且是毒力所必需的。拟议的研究将确定新药目标并增加我们对当前抗真菌药物作用的了解。定义内切酶体白色念珠菌中的功能也将为这些质膜结构域在其他病原真菌。