Identify virulence factors that facilitate Fusarium keratitis

确定促进镰刀菌角膜炎的毒力因子

• 批准号: 10164796
• 负责人: Li-Jun Ma
• 金额: $ 37.77万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164796
• 关键词: 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; Neutrophilic Infiltrate; Opportunistic Infections; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Plants; Plasmids; Population; Refractory; Reporting; Research; Rest; Severity of illness; Singapore; Specificity; Testing; Time; United States; Validation; Variant; Virulence; Virulence Factors; Work; alkalinity; 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

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 镰刀菌在环境中普遍存在，是农业病害的主要原因 国际吧临床上，镰刀菌属是人类疾病的偶然和偶然原因。然而，在这方面， 镰刀菌霉菌是真菌性角膜炎（和一般微生物性角膜炎）的最常见原因， 是发展中国家真菌性角膜炎患者致盲的主要原因。在工业化 2005年和2006年，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 新加坡。本建议将重点放在镰刀菌角膜炎使用的互补优势，在比较 PI Ma实验室的基因组学，以及我们的合作者Pearlman博士开发的镰刀菌角膜炎小鼠模型。 实验室比较基因组学研究主要集中在植物病原真菌F.尖孢菌分离株证明， 额外染色体（SP）的水平转移首次传递了植物寄主特异性 致病性最近的一项研究F.尖孢菌临床分离株显示四个独特的SP染色体， 证实，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 身体条件，如高温和碱性pH值和缺铁环境。鉴于这些 研究结果，我们假设某些适应性遗传性状是重要的建立镰刀菌 角膜炎和分隔型F.尖孢菌基因组，这些遗传性状很可能存在于 SP染色体。利用我们对SP染色体的理解，直接有助于真菌 致病性，该R 01项目将鉴定致病性SP染色体，并建立高通量 使用转录组学、正向/反向遗传学和 实验进化的方法。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。