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

真菌病原体对人类健康具有显著且日益增加的影响，并且缺乏有效的 治疗强调需要进一步研究。该提案将研究两种主要的病原体， 临床影响和最近真菌感染严重暴发的病例。在第一个目标中，我们将研究 两个大型的新型隐球菌临床队列，以确定毒力的遗传决定因素， 病原体的生态位适应。我们还将描述病原体基因表达的主要网站， 严重感染，并筛选和评估稳定额外染色体拷贝的突变， 真菌耐药的主要机制。在第二个目标中，我们将检查三个最近的真菌病例， 在美国暴发;将从临床病例中采集加特隐球菌和镰刀菌属的分离株 和环境，并进行测序，以检查环境水库如何与有毒菌株不同， 人类，类似于目标1中的工作，并进一步监测其中一种疫情如何在地理上传播 和时间最后，在目标3中，我们将研究C.白色念珠菌，常见的 念珠菌和最常见的真菌病原体，以及其他常见的念珠菌属 感染参与早期念珠菌检测和应答的初级先天免疫细胞。我们将使用 网络分析，以确定宿主-病原体枢纽，并研究这些网络如何在菌株之间演变 以及毒力和耐药性不同的物种。虽然这些目标是独立的项目， 研究真菌的发病机制，每个利用大规模测序，以扩大和发展新的范例 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.