The Genetic Basis of Virulence in Cryptococcus Neoformans

摘要 隐球菌属的病原真菌每年导致世界上近20万人死亡- 很宽。然而，并不是所有的隐球菌分离株都能引起致命性感染；有些是相对良性的 而另一些则是超强毒力。致病性的差异往往与变异有关。 在物种fic的形态和生理特征，如在高温下生长的能力。 酵母细胞周围的保护性多糖膜的大小，或对 抗真菌药物。为了增进对隐球菌生物学和隐球菌病的了解， 我们试图确定导致病毒变化的分离株和物种之间的遗传差异。 Lence和毒力相关性状，以解开遗传变异对基因网络的影响 以及支配这些特征的途径，并了解有助于 致病机理。 我们建议应用种群和数量基因组学方法以及微生物实验。 用心理进化论剖析沙门氏菌毒力及其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物种fic目的：目的1)建立作图种群和 对新生隐球菌、变态隐球菌进行数量性状基因座(QTL)定位 Mans和隐球菌Gattii，以确定导致毒力差异的基因和等位基因 特征和对抗真菌药物的抗药性；目标2)使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；以及目标3)利用性状作图和实验进化来识别 调节隐球菌与吞噬阿米巴相互作用的基因变体和TEST 这些变异是否与真菌病的细胞和动物模型中的毒力相关。

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.