Regulation of morphogenesis in C. albicans

描述（由申请人提供）： 由于新的医学治疗和人口老龄化增加了易感个体的数量，由白色念珠菌（最常见的人类真菌病原体）引起的致命性全身感染呈上升趋势。有一个迫切的需要，以改善这种不断升级的问题，因为目前的诊断程序和抗真菌药物的有效性有限的治疗管理。C.白色念珠菌是由其在宿主体内生长并传播到内部器官的能力引起的。这些过程的中心是质膜。这种基本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界面。质膜对于毒力的重要性被以下事实所强调，即它是最有效的抗真菌药物的直接或间接靶点。最近的研究 揭示了真菌质膜由离散的亚结构域组成，其在毒力和药物作用中的功能尚不清楚。因此，特定目标集中在新发现的质膜亚结构域，称为MCC/eisosomes。它们由整合膜蛋白（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 nm大小的点状斑块。我们的假设是，MCC/eisosomes是必要的适当的质膜功能，他们的分析将提供新的范式质膜组织和发病机制。初步研究表明，MCC蛋白Sur 7对形态发生、细胞壁完整性、侵入性生长和毒力具有广泛的重要性。另一个关键表型是sur 7？细胞对铜的敏感性超过1,000倍，这与富含铜的巨噬细胞吞噬体的生长减少有关。主要目标是鉴定这些结构域中的重要蛋白质（目标1），确定MCC/eisosomes的组装和拆卸如何受到药物的调节和干扰（目标2），并确定MCC/eisosomes在毒力中的作用（目标3）。这些结果有望通过鉴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，并改善更有效使用的前景。 公共卫生相关性：新的医学治疗和人口老龄化正在增加对由白色念珠菌（最常见的人类真菌病原体）引起的致命全身感染易感的个体。由于目前抗真菌药物的局限性，需要改进的治疗方法来解决这一日益严重的问题。对C.白念珠菌质膜是包围细胞的基本屏障，通过提供对当前抗真菌药物的更好理解和通过识别治疗干预的新靶点，预期将提高治疗成功率。

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.