Identify virulence factors that facilitate Fusarium keratitis

项目总结 镰刀菌在环境中随处可见，它们是农业疾病的主要原因。 全世界。在临床上，镰刀菌属是人类疾病的偶然和偶然原因。然而， 镰刀菌是引起真菌性角膜炎(和一般的微生物角膜炎)的最常见原因。 在发展中国家，真菌性角膜炎是导致患者失明的主要原因。在工业化中 在一些国家，2005年和2006年在美国一些地区报告了镰刀菌角膜炎的爆发 通常与真菌性角膜炎有关。英国、法国、香港和香港也报告了疫情。 新加坡。这项建议将重点放在镰刀菌角膜炎上，利用优势互补的比较 皮马实验室的基因组学，以及我们的合作者皮尔曼博士的小鼠镰刀菌角膜炎模型 实验室。比较基因组学研究集中在植物致病尖孢镰刀菌分离物上 第一次水平转移额外(SP)染色体传递植物寄主专一性 致病性。最近对一株尖孢镰刀菌临床分离株的研究发现，它有四条独特的SP染色体和 证实即使对于机会性感染，SP染色体也可能介导病原体对人类的适应 身体条件，如较高的温度和碱性酸碱度和缺铁环境。考虑到这些 结果，我们假设某些适应性遗传性状对镰刀菌的建立是重要的。 角膜炎和在分隔的尖孢镰刀菌基因组中，这些遗传特征可能出现在 SP染色体。利用我们对直接对真菌有贡献的SP染色体的理解 致病性，这项R01计划将鉴定致病SP染色体，并建立高通量 利用转录组学、正向/反向遗传学和基因工程技术筛选毒力因子 实验进化论方法。这些目标的实现将加深我们对分子机制的理解。 潜在的镰刀菌角膜炎，可用于开发新的抗真菌疗法。

PROJECT SUMMARY Fusarium molds are ubiquitous in the environment, where they are major causes of agricultural disease worldwide. Clinically, Fusarium species are incidental and accidental causes of human disease. However, Fusarium molds are the most common cause of fungal keratitis (and microbial keratitis in general) in developing countries and the leading cause of blindness among fungal keratitis patients. In industrialized countries, an outbreak of fusarium keratitis was reported in 2005 and 2006 in regions of the United States not usually associated with fungal keratitis. The outbreak was also reported in Britain, France, Hong Kong, and Singapore. This proposal will focus on fusarium keratitis using the complementary strengths in comparative genomics in PI Ma’s lab, and a murine model of fusarium keratitis developed at our collaborator Dr. Pearlman’s lab. Comparative genomics studies focused on plant pathogenic F. oxysporum isolates demonstrated for the first time that horizontal transfer of supernumerary (SP) chromosomes conveys plant host-specific pathogenicity. A recent study of a F. oxysporum clinical isolate revealed four unique SP chromosomes and confirmed that even for opportunistic infections, SP chromosomes may mediate pathogen adaptation to human body conditions, such as higher temperatures and alkaline pH and iron-poor environments. Given these findings, we hypothesize that certain adaptive genetic traits are important for the establishment of Fusarium keratitis and in the compartmentalized F. oxysporum genome, these genetic traits are likely to present in the SP chromosomes. Capitalizes on our understanding of SP chromosomes that contribute directly to fungal pathogenicity, this R01 project will identify pathogenic SP chromosomes, and establish high throughput screening pipeline to identify virulence factors using transcriptomics, forward/reverse genetics and experimental evolution approaches. The achieved aims will enhance our understanding molecular mechanisms underlying fusarium keratitis, which can be used to develop novel antifungal therapies.