Identify virulence factors that facilitate Fusarium keratitis

确定促进镰刀菌角膜炎的毒力因子

基本信息

批准号：
10630315
负责人：
Li-Jun Ma
金额：
$ 38.89万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630315
关键词：
Accidents Agriculture Antifungal Agents Antifungal Therapy Biological Phenomena Birth Blindness Candidate Disease Gene Cells Chromosome Transfer Chromosomes Clinical Complex Contact Lenses Cornea Coupled Couples DNA Resequencing Data Developed Countries Developing Countries Development Disease Disease Outbreaks Environment Event Evolution France Fusarium Genes Genetic Genetic Screening Genetic Transcription Genome Genotype Goals High temperature of physical object Hong Kong Human body Immune Immunocompetent Immunocompromised Host In Vitro Individual Infection Iron Keratitis Mediating Modeling Molds Molecular Monitor Mus Mutagenesis Mutation Neutrophil Infiltration Opportunistic Infections Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Plants Plasmids Population Refractory Reporting Research Rest Severity of illness Singapore Specificity Testing Time Tropical Climate United States Validation Variant Virulence Virulence Factors Work candidate identification climate zone comparative genomics disease phenotype drug development experimental study fungus genetic approach high throughput screening human disease human pathogen in vivo Model metatranscriptomics microbial mouse model multiple omics mutant new therapeutic target novel novel therapeutics pathogen phenomics reverse genetics sample fixation trait transcriptomics

项目摘要

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.

项目摘要镰刀菌在环境中无处不在，它们是农业疾病的主要原因全世界。临床上，镰刀菌种类是人类疾病的偶然和意外原因。然而，在发展中国家和真菌性角膜炎患者失明的主要原因。工业化国家，据报道，2005年和2006年在美国的地区爆发了镰刀菌爆发通常与真菌性角膜炎有关。在英国，法国，香港和新加坡。该提案将使用比较中的完整优势重点 Pi Ma的实验室中的基因组学，以及我们合作者Pearlman博士的镰刀菌角膜炎模型实验室。比较基因组学研究的重点是植物致病性F. oxysporum分离株，证明了第一次水平转移超级（SP）染色体传达植物宿主特异性致病性。最近对氧化菌孢子型临床分离株的研究揭示了四个独特的SP染色体和确认，即使对于机会性感染，SP染色体也可能介导病原体适应人类身体状况，例如较高的温度和碱性pH和贫困的环境。鉴于这些调查结果，我们假设某些适应性遗传特征对于建立镰刀菌很重要角膜炎和分室的氧气基因组中，这些遗传特征可能存在于 SP染色体。利用我们对直接有助于真菌造成的SP染色体的理解致病性，该R01项目将识别致病性SP染色体，并建立高吞吐量使用转录组学，正向/反向遗传学和实验进化方法。实现的目标将增强我们的理解分子机制基础镰刀菌角膜炎，可用于开发新型抗真菌疗法。