The Genetic Basis of Virulence in Cryptococcus Neoformans

新型隐球菌毒力的遗传基础

• 批准号: 10658925
• 负责人: JOSEPH HEITMAN
• 金额: $ 58.28万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-05 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658925
• 关键词: Affect; Alleles; Amoeba genus; Animal Model; Animals; Antifungal Agents; Basidiomycota; Benign; Biological Models; Biology; Cell model; Cells; Cellular Morphology; Cessation of life; Chemicals; Chromosome Mapping; Communities; Complement; Complex; Cryptococcosis; Cryptococcus; Cryptococcus gattii; Cryptococcus neoformans; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease; Drug resistance; Ecology; Environment; Etiology; Event; Evolution; Exhibits; Foundations; Funding; Fungal Drug Resistance; Genes; Genetic; Genetic Determinism; Genetic Epistasis; Genetic Transcription; Genetic Variation; Genetic study; Genomic approach; Genotype; High temperature of physical object; Human; Infection; Invaded; Maps; Medical; Methodology; Morbidity - disease rate; Morphology; Organ; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Phagocytes; Phenotype; Physiological; Polysaccharides; Population; Prevention; Public Health; Quantitative Trait Loci; Regulation; Research; Resources; Shapes; Signal Pathway; Signal Transduction; Sister; System; Testing; Tissues; Transcriptional Regulation; Variant; Virulence; Yeasts; capsule; comparative; fungus; gene network; genetic architecture; genetic resource; genetic variant; genome resource; insight; member; microbial; microorganism interaction; mortality; novel; novel strategies; novel therapeutic intervention; opportunistic pathogen; pathogen; pathogenic fungus; tool; trait

Abstract Pathogenic fungi of the genus Cryptococcus contribute to nearly 200,000 deaths annually world- wide. However, not all Cryptococcus isolates cause lethal infections; some are relatively benign whereas others are hypervirulent. Differences in pathogenicity are often correlated with variation in specific morphological and physiological features such as the ability to grow at high tempera- tures, the size of the protective polysaccharide capsule surrounding the yeast cell, or resistance to antifungal drugs. To advance the understanding of Cryptococcus biology and cryptococcal disease, we seek to identify genetic differences between isolates and species that lead to changes in viru- lence and virulence-related traits, to disentangle the effects of genetic variants on gene networks and pathways that govern such traits, and to understand the ecological interactions that contribute to pathogenesis. We propose to apply population and quantitative genomic approaches and microbial experi- mental evolution to dissect the genetic basis of variation in virulence and virulence-related traits in Cryptococcus. We propose three inter-related specific aims: Aim 1) Build mapping populations and carry out Quantitative Trait Locus (QTL) mapping in Cryptococcus neoformans, Cryptococcus deneofor- mans, and Cryptococcus gattii to identify genes and alleles that contribute to differences in virulence traits and resistance to anti-fungal drugs; Aim 2) Employ a novel chemical epistasis approach to dissect the impact of natural variation on signaling pathways and transcriptional networks that control virulence traits; and Aim 3) Utilize trait mapping and experimental evolution to identify genetic variants that modulate interactions between Cryptococcus and phagocytic amoeba and test whether these variants correlate with virulence in cellular and animal models of fungal disease.

摘要 隐球菌属的致病真菌每年导致全球近20万人死亡- 宽然而，并不是所有的隐球菌分离株都能引起致命感染，有些是相对良性的 而另一些是高毒性的。致病性的差异往往与变异有关 在特定的形态和生理特征，如在高温下生长的能力， 酵母细胞周围保护性多糖胶囊的大小，或对 抗真菌药物为了促进对隐球菌生物学和隐球菌病的理解， 我们试图确定分离株和物种之间的遗传差异，这些差异导致维鲁的变化， lence和毒力相关性状，以解开遗传变异对基因网络的影响 以及控制这些特征的途径，并了解有助于 发病机制 我们建议应用群体和定量基因组方法和微生物实验， 精神进化，剖析毒力和毒力相关性状变异的遗传基础， 隐球菌我们提出了三个相互关联的具体目标：目标1）建立映射群体， 在新生隐球菌、新生隐球菌和新生隐球菌中进行数量性状基因座（QTL）定位， 人类和格特隐球菌，以确定基因和等位基因，有助于毒力的差异， 性状和抗真菌药物的抗性;目的2）采用一种新的化学上位性方法， 剖析自然变异对信号通路和转录网络的影响， 控制毒力性状;和目的3）利用性状作图和实验进化来鉴定 调节隐球菌和吞噬阿米巴之间相互作用的遗传变异体和试验 这些变异是否与真菌疾病的细胞和动物模型中的毒力相关。