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

真菌病原体的基因组学：种群多样性、爆发和宿主反应

基本信息

批准号：
8710822
负责人：
Christina A Cuomo
金额：
$ 62.98万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-10 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8710822
关键词：
Aneuploidy Antifungal Therapy Area Australia Botswana California Candida Candida albicans Candidate Disease Gene Cells Cerebrospinal Fluid Chromosomes Clinical Clinical Research Communicable Diseases Copy Number Polymorphism Cryptococcus Cryptococcus neoformans Dendritic Cells Detection Disease Disease Outbreaks Drug resistance Environment Evaluation Evolution Fungal Drug Resistance Fusarium Gene Dosage Gene Expression Genes Genetic Genetic Determinism Genetic Recombination Genetic Variation Genome Genomics Geography Health Human Immune Immune response In Vitro Infection Large-Scale Sequencing Link Lung Maps Metadata Modeling Monitor Mutation Mycoses Outcome Pacific Northwest Partner in relationship Pathogenesis Pathway Analysis Pathway interactions Population Sampling Singapore Site Source Time United States Variant Virulence Virulent Work base cohort effective therapy genome sequencing in vivo macrophage mouse model novel pathogen response trait transcriptome sequencing

项目摘要

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.

真菌病原体对人类健康具有重大且日益严重的影响，但缺乏有效的治疗方法治疗强调需要进一步研究。该提案将检查两种具有大临床影响和最近严重爆发的真菌感染病例。在第一个目标中，我们将检查新型隐球菌的两个大型临床队列，以确定毒力的遗传决定因素和病原体的生态位适应。我们还将表征病原体基因在原发位点的表达严重感染，并筛选和评估稳定染色体额外拷贝的突变，真菌耐药性的主要机制。在第二个目标中，我们将研究最近发生的三个真菌病例美国爆发疫情；将从临床病例中采集格特隐球菌和镰孢菌的分离株和环境并进行测序，以检查环境储存库与毒力菌株有何不同人类，类似于目标 1 中的工作，并进一步监测其中一场疫情如何在地理范围内传播和时间。最后，在目标 3 中，我们将检查白色念珠菌（一种常见的细菌）的宿主和病原体界面。共生菌和最常见的真菌病原体，以及其他常见的念珠菌属物种感染参与早期念珠菌检测和反应的初级先天免疫细胞。我们将使用网络分析，以确定宿主-病原体中心并研究这些网络如何在菌株之间进化以及毒力和耐药性不同的物种。虽然这些目标代表独立项目检查真菌发病机制，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。