Exploring the mechanisms of fluconazole-induced aneuploidy in Cryptococcus neoformans

探索氟康唑诱导新型隐球菌非整倍体的机制

• 批准号: 9900826
• 负责人: Lukasz Kozubowski
• 金额: $ 21.99万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2022-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900826
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Aneuploidy; Architecture; Ascomycota; Azole resistance; Basidiomycota; Biochemical; Biological Models; Biology; Cause of Death; Cell Fraction; Cell division; Cells; Cellular biology; Centers of Research Excellence; Central Nervous System Diseases; Central Nervous System Fungal Infections; Cessation of life; Chromosomes; Cryptococcal Meningitis; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Diploidy; Disease; Drug resistance; Ergosterol; Eukaryota; Event; Exposure to; Fission Yeast; Flow Cytometry; Fluconazole; Fluorescence Microscopy; Fruit; Gene Dosage; Generations; Genetic Models; Genome; Goals; Health; Immune response; Immunocompetent; Immunocompromised Host; In Vitro; Infection; Lung infections; Meiosis; Microscopy; Mitotic; Mitotic Checkpoint; Modeling; Molecular; Molecular Biology; Morbidity - disease rate; Organism; Pathogenicity; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Ploidies; Polyploidy; Population; Production; Proteins; Public Health; Reporter; Reporting; Research; Resolution; Role; Saccharomyces cerevisiae; Saccharomycetales; Series; Stress; System; Techniques; Testing; Virulent; Work; Yeasts; cell growth; effective therapy; fungus; human disease; human pathogen; improved; in vivo; innovation; molecular array; nuclear division; pathogen; pathogenic fungus; response; segregation; tool

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.

项目摘要 真菌是免疫功能正常和免疫缺陷动物中死亡和发病的越来越重要的原因。 免疫功能低下的患者。由新型隐球菌引起的隐球菌性脑膜炎是最 真菌是世界上常见的中枢神经系统感染的原因。100万例隐球菌感染 艾滋病毒/艾滋病感染在全球范围内发生，主要是在艾滋病的情况下发生，占所有艾滋病相关死亡的三分之一。 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。最近的报告 表明基因组可塑性在C.新人类非整倍体形成的de- 减数分裂期间的novo增加了隐球菌种群的多样性，可能产生新的 毒性菌株在肺部感染过程中，隐球菌细胞变成多倍体， 宿主的免疫反应染色体拷贝数的变化是导致对细菌耐药性的原因。 唑类药物氟康唑的体内外研究。尽管有越来越多的证据表明非整倍体在 致病性C.关于控制新生儿免疫功能变化的分子机制， 染色体拷贝数。本提案的主要目的是阐明 在C.新形式主义特别强调 氟康唑治疗与非整倍体之间的关系我们将对氟康唑的作用进行详细的分析 对细胞生长和核分裂的影响此外，我们将阐明主轴组件的基本架构 检测点（SAC）途径。新生儿，并探讨这种途径的抑制是可能的， 氟康唑引发的非整倍体导致耐药性的原因之一。这项工作将有助于 我们对真菌病原体染色体变化的机制的理解， 感染