Functional Analysis of Regions of Introgression Between Species of Coccidioides

球孢子菌种间基因渗入区域的功能分析

• 批准号: 8487708
• 负责人: Bridget Marie Barker
• 金额: $ 16.39万
• 依托单位: TRANSLATIONAL GENOMICS RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487708
• 关键词: Affect; Arizona; Biological Process; California; Coccidioides; Coccidioides immitis; Coccidioides posadasii; Coccidioidomycosis; Data; Exhibits; Gene Deletion; Gene Proteins; Genes; Genetic; Genetic Recombination; Genome; Health Services; Hypersensitivity skin testing; Hypoxia; Immunocompetent; In Vitro; Inbred BALB C Mice; Infection; Iron; Knowledge; Lead; Messenger RNA; Metalloproteases; Metalloproteinase Gene; Methods; Mexico; Modeling; Morbidity - disease rate; Mus; Nature; Organism; Oxidative Stress; Pathogenesis; Patients; Pattern; Phase; Population; Reporting; Role; Signal Transduction; South America; Testing; Texas; Time; Transcript; Variant; Virulence; Virulence Factors; base; desert fever; in vivo; interest; mortality; novel therapeutics; novel vaccines; pathogen; public health relevance; reconstitution; vaccine candidate

DESCRIPTION (provided by applicant): Coccidioides immitis and C. posadasii are filamentous fungal pathogens and causal agents of Valley Fever, or coccidioidomycosis. These pathogens are increasingly responsible for significant morbidity and mortality in immunocompetent patients. Over the past several years, Valley Fever cases have increased dramatically. The genus Coccidioides was recently recognized as two species. The two species are divided into at least two populations: northern and southern California for C. immitis, and Arizona/Mexico and Texas/South America for C. posadasii. The nature of the species and population boundaries are of particular interest due to the recent discovery of hybridization and introgression within Coccidioides. Multiple putative hybridization regions were located in several genomes analyzed. However, one particular region of introgression represents a unique opportunity to assess genes that are highly likely to be relevant for species-specific virulence and adaptation to mammalian hosts. This region has a shared recombination point flanking a metalloproteinase gene MEP4, genes that are highly expressed in the parasitic phase, as well as genes of unknown function. Importantly, evolutionary selection has preserved this region in multiple strains of C. immitis further emphasizing the likely role in virulence of these genes. Variation among strains for virulence in murine models of coccidioidomycosis has been observed, but has not been tested in the context of the newly discovered species or with a focused targeted underlying genetic mechanism hypothesis to test. Regardless of whether these genes are responsible for the increased infection rate observed in Arizona, which is possible, functional characterization of these genes will significantly expand our knowledge of Coccidioides pathogenesis mechanisms which may lead to novel vaccine candidates and/or new therapeutic options. In this proposal, the function and role of the genes and proteins in this introgressed region will be analyzed to determine their importance in fungal virulence and host interactions.

描述（由申请人提供）：球虫下炎和c。posadasii是山谷热的丝状真菌病原体和因果剂，或球虫菌病。这些病原体越来越负责免疫能力患者的发病率和死亡率。在过去的几年中，山谷热病例急剧增加。最近将球虫属属公认为是两个物种。这两种物种至少分为两个人群：北加州的侵入性炎，亚利桑那州/墨西哥和德克萨斯州/南美c。posadasii。由于最近在球球菌中发现了杂交和渗入，物种和种群边界的性质特别感兴趣。多个推定的杂交区域位于分析的几个基因组中。但是，一个特定的渗入区域代表了评估基因的独特机会，这些基因很可能与物种特异性的毒力和对哺乳动物宿主的适应性相关。该区域具有共同的重组点，其侧面是金属蛋白酶基因MEP4，该基因在寄生相中高度表达，以及功能未知的基因。重要的是，进化选择将该区域保存在多种菌株中，进一步强调了这些基因毒力中的可能作用。已经观察到了球虫菌病的鼠模型中毒力的菌株之间的变化，但尚未在新发现的物种的背景下进行测试，或者以重点针对的靶向潜在遗传机制假设进行测试。不管这些基因是否导致亚利桑那州观察到的感染率提高，这是可能的，这些基因的功能表征将大大扩展我们对Coccidioides发病机制的了解，这可能导致新的候选疫苗候选和/或新的治疗选择。在此提案中，将分析基因和蛋白质在该侵入区域中的功能和作用，以确定它们在真菌毒力和宿主相互作用中的重要性。