Functional Analysis of Regions of Introgression Between Species of Coccidioides

描述(申请人提供)：球孢子虫和假球孢子虫是引起谷热或球孢子菌病的丝状真菌病原体和病原体。这些病原体越来越多地导致免疫能力患者的显著发病率和死亡率。在过去的几年里，山谷热病例急剧增加。球藻属(Coccidioids)最近被确认为两个种。这两个种至少被分成两个种群：加州北部和南部的伊米提斯，以及亚利桑那州/墨西哥和德克萨斯州/南美洲的波萨迪斯。由于最近在球孢子虫中发现了杂交和渗入，物种的性质和种群边界特别令人感兴趣。在分析的几个基因组中定位了多个可能的杂交区。然而，一个特定的导入区域代表了一个独特的机会来评估与物种特定毒力和对哺乳动物宿主的适应高度相关的基因。这个区域有一个共同的重组点，位于金属蛋白酶基因MEP4的两侧，这些基因在寄生期高表达，以及功能未知的基因。重要的是，进化选择在多个免疫球虫菌株中保存了这一区域，进一步强调了这些基因在毒力中的可能作用。在球孢子菌病的小鼠模型中，已经观察到菌株之间的毒力差异，但还没有在新发现的物种的背景下进行测试，或者使用有针对性的潜在遗传机制假说进行测试。无论这些基因是否与亚利桑那州观察到的感染率增加有关(这是可能的)，这些基因的功能特征将极大地扩展我们对球虫致病机制的了解，这可能导致新的候选疫苗和/或新的治疗方案。在这项建议中，将分析基因和蛋白质在这个导入区域的功能和作用，以确定它们在真菌毒力和宿主相互作用中的重要性。

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.