Genomic and Transcriptomic Analysis of Invasive Fungal Pathogens

总结/摘要 有一个急剧上升的数量严重的真菌感染由于不断增加， 免疫功能低下的人数。真核生物的基本代谢 真菌和哺乳动物细胞之间的通路阻碍了抗真菌剂的发展， 许多有效抑制真菌生长的化合物对宿主细胞也是有毒的。越来越清楚的 单独使用新型抗真菌药物不太可能显著降低真菌感染的死亡率 没有新的治疗方法的帮助。有希望的替代方法包括将当前的 使用增强宿主免疫系统消除微生物的能力的药剂进行抗真菌治疗， 破坏了控制入侵的物种间分子相互作用。这些方法需要详细的 了解宿主和病原体之间复杂的相互作用。该提案将侧重于三个方面 新出现的真菌病原体- Scedosporium spp、耳念珠菌和毛霉目真菌。感染这些 三种遗传学上不同的病原体经常对目前可用的抗真菌治疗无效， 因此与极高的死亡率有关。在这里，我们将联合收割机双物种RNA-seq， 比较基因组分析，建立动物模型和真菌遗传学， 全面分析每一类的宿主-病原体相互作用。分析这三种不同类型的 真菌使用相同的方法将使我们能够确定共同点以及关键的差异， 以及它们在宿主中引起的反应。拟议的研究将提供大量信息， 关于真菌和宿主中的基因功能和调节，并可能导致鉴定 新的治疗靶点来治疗这种日益严重的人类疾病。

SUMMARY/ABSTRACT There has been a dramatic rise in the number of severe fungal infections due to a constant increase in the number of individuals who are immunocompromised. Strong similarities in the basic eukaryotic metabolic pathways between fungi and mammalian cells have hindered the development of antifungal agents because many compounds that are effective at inhibiting fungal growth are also toxic to host cells. It is becoming clear that novel antifungal agents alone are unlikely to significantly reduce the mortality rate of fungal infections without the aid of new therapeutic approaches. Promising alternative approaches include combining current antifungal treatments with agents that enhance the host immune system's ability to eliminate the microbe or disrupt an interspecies molecular interaction that governs invasion. These approaches require a detailed understanding of the complex interaction between host and pathogen. This proposal will focus on three emerging fungal pathogens - Scedosporium spp, Candida auris and Mucorales fungi. Infections with these three phylogenetically distinct pathogens frequently fail to respond to currently available antifungal therapy and are therefore associated with extremely high mortality rates. Here we will combine dual-species RNA-seq, comparative genome analysis, established animal models and fungal genetics to systematically and comprehensively analyze the host-pathogen interactions for each class. Analyzing all three different types of fungi using the same approach will enable us to define commonalities as well as key differences among the organisms and the responses they elicit in the host. The proposed studies will provide a wealth of information regarding gene function and regulation in both the fungus and the host and will likely lead to the identification of novel therapeutic targets to treat this increasingly serious cause of human disease.