Genomics of fungal pathogens: population diversity, outbreaks, and host response

真菌病原体对人类健康的影响越来越大，而且缺乏有效的 治疗方法突出了进一步研究的必要性。这项提案将对这两种主要病原体进行大规模检查 真菌感染的临床影响和最近的严重暴发病例。在第一个目标中，我们将检查 两个新隐球菌的大型临床队列，以确定毒力和遗传决定因素 病原体的生态位适应。我们还将表征病原体基因在主要部位的表达。 严重感染，同时筛查和评估稳定额外染色体副本的突变， 真菌耐药的主要机制。在第二个目标中，我们将检查最近的三个真菌病例 美国暴发；将从临床病例中提取隐球菌和镰刀菌的分离株 和环境，并进行测序，以检查环境水库与毒力强的菌株在 人类，类似于在AIM 1中的工作，并进一步监测这些疫情是如何在地理上传播的 还有时间。最后，在目标3中，我们将检查白念珠菌的宿主和病原体之间的界面，这是一种常见的 共生菌和最常见的真菌病原体，以及其他常见的观察到的念珠菌 感染初级先天免疫细胞参与了念珠菌的早期检测和反应。我们将使用 网络分析以识别宿主-病原体中心并研究这些网络如何在菌株之间进化 以及毒力和抗药性不同的物种。虽然这些目标代表独立的项目，以 研究真菌的发病机制，每个都利用大规模测序来扩展和开发新的范例 用于真菌毒力的基因组分析。

Fungal pathogens have a significant and increasing impact on human health-, and the lack of effective treatments highlight the need for further study. This proposal will examine both major pathogens with large clinical impacts and recent cases of severe outbreaks of fungal infections. In the first aim, we will examine two large clinical cohorts of Cryptococcus neoformans, to define the genetic determinants of virulence and niche adaptation in the pathogen. We will also characterize pathogen gene expression at the primary site of severe infection, and both screen for and evaluate mutations that stabilize extra copies of chromosomes, a major mechanism of fungal drug resistance. In the second aim, we will examine three recent cases of fungal outbreaks in the US; isolates of Cryptococcus gattii and Fusarium spp will be sampled from clinical cases and the environment and sequenced to examine how environmental reservoirs differ from strains virulent in humans, similar to work in aim 1, and further monitor how one of these outbreaks spread over geography and time. Lastly in aim 3, we will examine the host and pathogen interface for C. albicans, a common commensal and the most common fungal pathogen, and other commonly observed Candida species infecting the primary innate immune cells involved in early Candida detection and response. We will use network analysis to identify host-pathogen hubs and to study how these networks evolve between strains and species differing in virulence and drug resistance. While these aims represent independent projects to examine fungal pathogenesis, each utilizes large-scale sequencing to extend and develop new paradigms for genomic analysis of fungal virulence.