Regulation of morphogenesis in C. albicans

描述(申请人提供)：由白色念珠菌引起的致命性全身感染是人类最常见的真菌病原体，随着新的治疗方法和人口老龄化增加了易感人群的数量，这种感染呈上升趋势。由于目前的诊断程序和抗真菌药物的有效性有限，因此迫切需要改进对这一不断升级的问题的治疗管理。白色念珠菌的致病作用是由其在宿主内生长并传播到内脏器官的能力引起的。这些过程的中心是质膜。这种基本的屏障调节毒力因子的分泌、形态发生、细胞壁的合成以及与细胞外环境的接口。质膜是最有效的抗真菌药物的直接或间接靶标，这一事实突显了质膜对毒力的重要性。最新研究 揭示了真菌质膜由离散的亚区组成，其在毒力和药物作用中的功能尚不清楚。因此，特定的目标集中在新发现的称为MCC/eisosome的质膜亚域上。它们由完整的膜蛋白(MCC部分)和邻近的外周膜蛋白(Eisosome)组成。这些独特的结构域不同于脂筏，因为它们是与膜内陷相关的稳定的300纳米大小的点状斑块。我们的假设是，MCC/Eisosome对于质膜的正常功能是必不可少的，它们的分析将为质膜组织和发病机制提供新的范式。为了支持这一点，初步研究表明，MCC蛋白Sur7对形态发生、细胞壁完整性、侵袭性生长和毒力具有广泛的重要性。另一个关键的表型是，Sur7细胞对铜的敏感性是1000倍，这与富含铜的巨噬细胞吞噬小体生长减少有关。主要目标是确定这些结构域中的重要蛋白质(目标1)，确定MCC/Eisosome的组装和拆解是如何调节的，以及如何被药物干扰(目标2)，以及确定MCC/Eisosome在毒力中的作用(目标3)。这些结果有望通过确定真菌发病机制中新的质膜功能来帮助开发新的治疗方法。此外，这些结果将增加我们对当前抗真菌药物的了解，并改善更有效的使用前景。

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.