Exploring the mechanisms of fluconazole-induced aneuploidy in Cryptococcus neoformans

项目总结 真菌是免疫系统疾病死亡和发病的一个日益重要的原因 免疫功能受损的病人。由新生隐球菌引起的隐球菌性脑膜炎最多 世界上真菌中枢神经系统感染的常见原因。100万例隐球菌病 感染发生在全球，主要发生在艾滋病的背景下，占所有与艾滋病相关的死亡人数的三分之一。 尽管存在这些公共卫生威胁，但对隐球菌病的有效治疗是不够的。最近的报道 提示基因组可塑性在新生葡萄球菌致病中的重要作用。非整倍体形成去整倍体 减数分裂期间的Novo增加了隐球菌种群的多样性，可能会产生新的 毒力强的菌株。在肺部感染期间，隐球菌细胞变成多倍体，这保护它们免受 宿主的免疫反应。染色体拷贝数的变化是产生抗病的原因 唑类药物氟康唑的体内外研究。尽管越来越多的证据表明非整倍体在 新生隐孢子虫的致病性对其致病性的分子机制了解甚少 染色体拷贝数这种有机体中的染色体拷贝数这项提议的主要目的是阐明机制。 负责产生新生隐孢子虫的非整倍体，并特别强调连接 氟康唑治疗和非整倍体之间的关系。我们将对氟康唑的疗效进行详细的分析 对细胞生长和核分裂的影响。此外，我们还将阐明主轴组件的基本结构 检查点(SAC)途径，并探讨该途径被抑制的可能性。 氟康唑引发非整倍体导致耐药的原因之一。这项工作将有助于 我们对一种真菌病原体染色体变化机制的理解 感染。

PROJECT SUMMARY Fungi are an increasingly important cause of death and morbidity in both immunocompetent and immunocompromised patients. Cryptococcal meningitis caused by Cryptococcus neoformans is the most common cause of fungal central nervous system infection in the world. One million cases of Cryptococcal infection occur globally, largely in the context of AIDS and constitute one-third of all AIDS-associated deaths. Despite these public health threats, effective treatments for cryptococcosis are inadequate. Recent reports indicate a high importance of genome plasticity in the pathogenicity of C. neoformans. Aneuploidy formed de- novo during meiotic divisions adds to the diversity of cryptococcal population potentially generating new virulent strains. During pulmonary infection, cryptococcal cells become polyploids, which protects them from the host immune response. Changes in chromosomal copy number are responsible for the resistance to the azole drug fluconazole in vitro and in vivo. Despite mounting evidence that aneuploidy is crucial in pathogenicity of C. neoformans very little is known about the molecular mechanisms that govern changes in chromosomal copy number in this organism. The main objective of this proposal is to elucidate mechanisms responsible for generation of aneuploidy in C. neoformans with a particular emphasis on the connection between fluconazole treatment and aneuploidy. We will perform a detailed analysis of the effects of fluconazole on cell growth and nuclear division. In addition, we will elucidate basic architecture of the spindle assembly checkpoint (SAC) pathway in C. neoformans, and explore the possibility that the inhibition of this pathway is one of the causes of fluconazole-triggered aneuploidy leading to drug resistance. This work will contribute to our understanding of the mechanisms that are involved in chromosomal changes of a fungal pathogen during infection.