Regulation of morphogenesis in C. albicans

白色念珠菌形态发生的调控

• 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
• 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

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