Functional Analysis of Regions of Introgression Between Species of Coccidioides

性状（由申请方提供）：粗球孢子菌和粗球孢子菌。posadasii是丝状真菌病原体和山谷热或球孢子菌病的致病因子。这些病原体越来越多地导致免疫功能正常的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。球孢子菌属最近被确认为两个种。这两个物种至少可分为两个种群：北方和加州南部的C。immitis，亚利桑那/墨西哥和德克萨斯/南美洲为C. posadasii。由于最近发现球孢子菌属内的杂交和渐渗，物种和种群边界的性质特别令人感兴趣。多个假定的杂交区域位于几个基因组分析。然而，一个特定区域的基因渗入代表了一个独特的机会，以评估基因是非常有可能是相关的物种特异性的毒力和适应哺乳动物宿主。该区域有一个共同的重组点，侧翼的金属蛋白酶基因MEP 4，在寄生阶段高度表达的基因，以及未知功能的基因。重要的是，进化选择在多株C. immitis进一步强调了这些基因在毒力中的可能作用。已观察到球孢子菌病小鼠模型中菌株间的毒力变异，但尚未在新发现的种属背景下进行测试，也未采用重点靶向潜在遗传机制假设进行测试。无论这些基因是否是导致亚利桑那州感染率增加的原因（这是可能的），这些基因的功能表征将显著扩展我们对球孢子菌致病机制的了解，这可能导致新的候选疫苗和/或新的治疗选择。在这个建议中，基因和蛋白质的功能和作用，在这个渗入区域将进行分析，以确定其在真菌毒力和宿主相互作用的重要性。

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.