Genomic and Transcriptomic Analysis of Invasive Fungal Pathogens

摘要/摘要 严重真菌感染的数量急剧上升，这是由于 免疫功能受损的个体数量。真核生物的基本代谢有很大的相似性 真菌和哺乳动物细胞之间的通路阻碍了抗真菌药物的发展，因为 许多有效抑制真菌生长的化合物对宿主细胞也是有毒的。事情正在变得明朗起来 仅靠新的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现有的 抗真菌治疗，可增强宿主免疫系统清除微生物或 破坏控制入侵的物种间分子相互作用。这些方法需要详细的 了解寄主和病原体之间的复杂相互作用。这项提案将重点放在三个方面 新出现的真菌病原体--塞多孢菌、金黄色念珠菌和毛霉菌。感染了这些病毒 三种在系统发育上截然不同的病原体经常对目前可用的抗真菌疗法无效， 因此与极高的死亡率有关。在这里，我们将结合双物种RNA-seq， 比较基因组分析，已建立的动物模型和真菌遗传学，以系统和 综合分析每一类的寄主-病原菌相互作用。分析所有三种不同类型的 使用相同方法的真菌将使我们能够定义 生物体以及它们在宿主体内引起的反应。拟议的研究将提供丰富的信息。 关于真菌和寄主中的基因功能和调控，并可能导致鉴定 治疗这一日益严重的人类疾病的新的治疗靶点。

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.