Plasma membrane promotes stress resistance and virulence of Candida albicans

项目摘要 人类真菌病原体白色念珠菌是医院获得性血流的主要原因 感染，并可以传播成为致命的。迫切需要改进治疗方法。 管理C。白色念珠菌感染，因为目前的抗真菌药物的有效性有限， 抗药性菌株正在出现。C.白色念珠菌是由它的能力， 在宿主体内生长并扩散到内部器官。细胞膜是至关重要的 对于这些过程，因为这一基本屏障介导了广泛的功能， 毒力包括细胞壁合成、毒力因子分泌、形态发生和营养 摄取。质膜的重要性突出的事实是，它是大多数的目标， 目前使用的抗真菌药物和许多抗菌肽。因此，更好地理解 质膜组织和功能的研究有助于设计新的治疗方法， 治疗和提高目前抗真菌药物的有效性。为了弥补这一差距， 知识，目的是利用最新的发现，以确定新的机制 质膜保护C.白色念珠菌从宿主的压力条件。目标1是 定义了保护质膜免受宿主氧化爆发的机制， 可引起脂质过氧化的连锁反应，破坏膜的完整性。这些研究将 利用我们最近发现的一种保护C.抗脂质过氧化作用。 目标2将定义PM如何抵抗由产生的HOCl（次氯酸;漂白剂）引起的压力 中性粒细胞氧化爆发期间髓过氧化物酶的作用。虽然中性粒细胞是众所周知的， 产生HOCl，关于它对质膜的影响以及C.白色念珠菌保护 目标3是定义C.白色念珠菌PM在抗铜和细胞壁中起关键作用 压力，这也是在吞噬体中遇到的。这一目标利用了我们的发现， 被称为eisosomes或MCC域的专门质膜亚域促进适当的PM 所需的抗铜和细胞壁应力的结构。定义C.白色念珠菌血浆 膜抵抗压力有望揭示新的发病机制，这将有助于未来 研究开发新的治疗方法，并增加我们对当前 抗真菌药物，以提高其更有效地使用的前景。

Project Summary The human fungal pathogen Candida albicans is a leading cause of hospital-acquired bloodstream infections and can disseminate to become lethal. 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. The plasma membrane is fundamentally important for these processes, as this essential barrier mediates a wide range of functions that are critical for virulence including cell wall synthesis, secretion of virulence factors, morphogenesis, and nutrient uptake. The importance of the plasma membrane is highlighted by the fact that it is the target for most of the currently used antifungal drugs and many antimicrobial peptides. Therefore, a better understanding of plasma membrane organization and function is needed to facilitate the design of new therapeutic treatments and to increase the effectiveness of current antifungal drugs. To address this gap in knowledge, the Aims are designed to take advantage of recent discoveries to identify novel mechanisms by which the plasma membrane protects C. albicans from stressful conditions in the host. Aim 1 is to define the mechanisms that protect the plasma membrane against the oxidative burst in the host, which can cause a chain reaction of lipid peroxidation that destroys membrane integrity. These studies will leverage our recent identification of a new pathway that protects C. albicans against lipid peroxidation. Aim 2 will define how the PM resists stress caused by HOCl (hypochlorous acid; bleach) that is produced by myeloperoxidase during the neutrophil oxidative burst. Although neutrophils are well known to produce HOCl, little is known about its effects on the plasma membrane or how C. albicans protects against it. Aim 3 is to define how the C. albicans PM plays a key role in resisting copper and cell wall stress, which are also encountered in the phagosome. This aim takes advantage of our discovery that specialized plasma membrane subdomains known as eisosomes or MCC domains promote proper PM architecture needed for resistance to copper and cell wall stress. Defining how the C. albicans plasma membrane resists stress is expected to reveal novel mechanisms of pathogenesis that will aid future studies in development of new therapeutic approaches and increase our understanding of current antifungal drugs to improve the prospects for their more effective use.