Comparative and functional genomics of C. neoformans

项目摘要/摘要。最近的估计表明，脑膜脑炎是由 在艾滋病患者的死亡中，有15%是由真菌新生隐球菌造成的。与其他真菌一起 因此，新生梭菌是对全世界3700万艾滋病毒携带者的主要威胁。一个 最初被命名为隐球菌属的相关物种复合体最近已成为主要的 免疫能力强的人的病原体。我们研究计划的长期目标是获得 将导致抗击隐球菌感染的新战略的知识。特别是，我们正在努力 详细了解真菌在脊椎动物宿主中繁殖所需的因素。在……里面 具体地说，我们寻求确定新的治疗目标。我们的重点是铁作为一种基本的营养物质 病原菌的增殖和寄主环境的重要指标。铁尤其重要 因为哺乳动物通过一种称为营养免疫的过程主动阻止病原体摄入铁。 因此，病原体必须能够成功地竞争铁才能导致疾病。我们有 研究表明，铁影响新生葡萄球菌的生长，也影响多糖胶囊的大小， 是主要的致病因素。我们的努力集中在表征铁感应的机制上。 以及利用监管信息来确定收购铁矿石所需的目标。第一个具体目标 是将单硫醇谷氧还蛋白Grx4表征为铁有效性的关键传感器。Grx4与 铁调节因子Cir1及其蛋白调控铁的动态平衡和毒力因子的表达。 我们试图了解铁感应的机制以及铁信号如何影响基因表达。 第二个特定目标是研究Grx4与转录因子网络的相互作用。二 已经确定了强有力的候选者(HapX和Gat201)以及它们之间的相互作用和监管影响 这些带有Grx4的蛋白质将被鉴定。最终的具体目标是基于高生产力的基因 筛选确定细胞内运输血红素的机制的组件。突变体缺失 将构建获得血红素的传输函数，并在小鼠吸入模型中进行测试 隐球菌病。此外，还开发了一种血红素传感器，以检测贩运过程中是否存在血红素。 在不同宿主组织位置的培养和增殖过程中的隐球菌细胞中的突变体。总的来说， 这些研究将提供铁感应与摄取调节相结合的综合观点。 在隐球菌病期间至关重要的策略。 好了！

Project Summary/Abstract. Recent estimates indicate that meningoencephalitis caused by the pathogenic fungus Cryptococcus neoformans is responsible 15% of deaths in AIDS patients. Along with other fungal pathogens, C. neoformans is therefore a major threat to the 37 million people worldwide living with HIV. A complex of related species originally designated Cryptococcus gattii has recently emerged as a primary pathogen of immunocompetent people. The long-term goal of our research program is to acquire knowledge that will lead to new strategies to combat cryptococcal infections. In particular, we are working to acquire a detailed understanding of the factors required for fungi to proliferate in vertebrate hosts. In particular, we seek to identify new targets for therapy. Our focus is on iron as an essential nutrient for pathogen proliferation and an important indicator of the host environment. Iron is especially important because mammals actively withhold iron from pathogens through a process called nutritional immunity. Pathogens must therefore be able to successfully compete for iron in order to cause disease. We have shown that iron influences the growth of C. neoformans and also the size of the polysaccharide capsule that is the major virulence factor. Our efforts have focused on characterizing the mechanisms of iron sensing and exploiting the regulatory information to identify targets required for iron acquisition. The first specific aim is to characterize the monothiol glutaredoxin Grx4 as a key sensor of iron availability. Grx4 interacts with the iron regulator Cir1 and the proteins regulate iron homeostasis and the expression of virulence factors. We seek to understand the mechanisms of iron sensing and how the iron signal influences gene expression. A second specific aim will investigate the interaction of Grx4 with a network of transcription factors. Two strong candidates have been identified (HapX and Gat201) and the interactions and regulatory influences of these proteins with Grx4 will be characterized. A final specific aim is based on highly productive genetic screens that identified components of the intracellular machinery for heme trafficking. Mutants lacking trafficking functions for heme acquisition will be constructed and tested in mouse inhalation models of cryptococcosis. Additionally, a heme sensor has been developed to detect heme availability in trafficking mutants in culture and in cryptococcal cells during proliferation in different host tissue locations. Overall, these studies will provide a comprehensive view the integration of iron sensing with the regulation of uptake strategies that are critical during cryptococcosis. !