Regulation of morphogenesis in C. albicans

描述（由申请人提供）：白色念珠菌是最常见的人类真菌病原体，随着新的医学治疗和人口老龄化，易感人群的增加，白色念珠菌引起的致命全身感染呈上升趋势。由于目前的诊断程序和抗真菌药物的有效性有限，迫切需要改善对这一日益严重的问题的治疗管理。白色念珠菌的致病作用是由其在宿主体内生长和传播到内脏的能力引起的。这些过程的中心是质膜。这一重要屏障介导毒力因子的分泌、形态发生、细胞壁合成以及与细胞外环境的交互作用。质膜是最有效的抗真菌药物的直接或间接靶标，这一事实强调了质膜对毒力的重要性。最近的研究

DESCRIPTION (provided by applicant): Lethal systemic infections caused by Candida albicans, the most common human fungal pathogen, are on the rise as new medical treatments and an aging population are increasing the pool of susceptible individuals. There is an urgent need to improve the therapeutic management of this escalating problem since current diagnostic procedures and antifungal drugs have limited effectiveness. 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. This essential barrier mediates secretion of virulence factors, morphogenesis, cell wall synthesis, and interfaces with the extracellular environment. The importance of the plasma membrane for virulence is underscored by the fact that it is directly or indirectly the target of the most effective antifungal drugs. Recent studies revealed that fungal plasma membranes are composed of discrete subdomains whose function in virulence and drug action is not known. Therefore, the Specific Aims are focused on the newly discovered plasma membrane subdomains called MCC/eisosomes. They consist of integral membrane proteins (MCC portion) and adjacent peripheral membrane proteins (eisosome). These unique domains are distinct from lipid rafts in that they are stable 300 nm-sized punctate patches that are associated with membrane invaginations. Our hypothesis is that MCC/eisosomes are essential for proper plasma membrane function and that their analysis will provide new paradigms for plasma membrane organization and the mechanisms of pathogenesis. In support of this, preliminary studies demonstrate that the MCC protein Sur7 is broadly important for morphogenesis, cell wall integrity, invasive growth, and virulence. Another key phenotype is that sur7¿ cells are >1,000-fold sensitive to copper, which correlates with decreased growth in macrophage phagosomes that are enriched in copper. The major goals are to identify the important proteins in these domains (Aim 1), to determine how the assembly and disassembly of MCC/eisosomes is regulated and can be perturbed by drugs (Aim 2), and to define the roles of MCC/eisosomes in virulence (Aim 3). The results are expected to aid development of new therapeutic approaches by identifying novel plasma membrane functions in fungal pathogenesis. Furthermore, these results will increase our understanding of current antifungal drugs and improve the prospects for more effective use. PUBLIC HEALTH RELEVANCE: New medical treatments and an aging population are increasing the pool of individuals that are susceptible to lethal systemic infections caused by Candida albicans, the most common human fungal pathogen. Improved therapeutic approaches are needed to meet this escalating problem due to the limitations of current antifungal drugs. The proposed studies on the C. albicans plasma membrane, the essential barrier that surrounds the cell, are expected to improve therapeutic success by providing a better understanding of current antifungal drugs and by identifying new targets for therapeutic intervention.