Host-specific cell surface receptors on African trypanosomes

描述（由申请人提供）：鞭毛原生动物寄生虫布鲁氏锥虫是导致非洲锥虫病的原因，该疾病在撒哈拉以南非洲地区导致人类和牲畜的广泛死亡和发病率。昏睡病如果不治疗是致命的，但目前还没有疫苗，目前的治疗方法陈旧、有毒且难以实施。因此，迫切需要进行研究以更好地了解这些寄生虫并促进新的治疗干预措施的发展。布鲁氏体在哺乳动物和采采蝇宿主之间交替存在，并且必须整合来自外部环境的信号才能在两个宿主中生存、发育和发病。寄生虫表面蛋白保护宿主免受免疫防御，允许获取营养物质，并提供对宿主-寄生虫相互作用和发病机制重要的感觉和信号功能。因此，细胞表面蛋白对布鲁氏体的寄生生活方式至关重要，并成为昏睡病治疗干预的有吸引力的靶点。迄今为止，还没有对寄生虫表面蛋白质组进行系统的研究，关键的表面暴露蛋白大部分仍然未知。这表明我们对锥虫生物学和宿主-寄生虫界面的理解存在重大差距。通过结合细胞表面蛋白的亲和纯化与最先进的蛋白质组学和分离完整鞭毛的开创性方法，我们现在能够定义布鲁氏体的表面蛋白质组，包括专门用于信号传导和宿主-寄生虫相互作用的表面亚结构域。我们的目标是利用我们的蛋白质组学方法，从昆虫和哺乳动物的寄生虫血液中定义布鲁氏体细胞表面的完整蛋白质库。从这些数据和我们的鞭毛蛋白质组，我们将确定宿主特异性表面蛋白，将测试其对哺乳动物宿主感染的影响。虽然我们的研究重点是布鲁氏体的宿主-寄生虫界面，但我们希望我们的研究结果能对寄生虫原生动物的基础生物学和发病机制的研究产生广泛的兴趣。

DESCRIPTION (provided by applicant): The flagellated protozoan parasite Trypanosoma brucei is responsible for African trypanosomiasis, which causes widespread mortality and morbidity of humans and livestock in sub-Saharan Africa. Sleeping sickness is fatal if untreated, yet no vaccine exists and current treatments are old, toxic and difficult to administer. Thus, there is a pressing need for research to better understand these parasites and facilitate development of new therapeutic interventions. T. brucei alternates between mammalian and tsetse fly hosts and must integrate signals from the external environment for survival, development and pathogenesis in both hosts. Parasite surface proteins protect against host immune defenses, allow acquisition of nutrients and provide sensory and signaling functions important for host-parasite interactions and pathogenesis. Cell surface proteins are thus critical for the parasitic life-style of T. brucei and make attractive targets for therapeutic intervention in sleeping sickness. To date, no systematic study of the parasite surface proteome has been conducted and key surface-exposed proteins remain mostly unknown. This represents a major gap in our understanding of trypanosome biology and the host-parasite interface. By combining affinity purification of cell surface proteins with state-of-the-art proteomics and a pioneering method for isolating intact flagella, we are now able to define the surface proteome of T. brucei, including surface sub-domains that are specialized for signaling and host-parasite interaction. Our goals are to capitalize on our proteomics approach to define the complete protein repertoire of the T. brucei cell surface from insect and mammalian bloodstream form parasites. From these data and our flagellum proteome, we will identify host-specific surface proteins, which will be tested for an impact on infection of the mammalian host. While our focus is on the host-parasite interface of T. brucei, we expect our results to be of wide interest for the community studying fundamental biology and pathogenesis of parasitic protozoa. PUBLIC HEALTH RELEVANCE: African trypanosomes are devastating human and animal pathogens that cause significant human mortality and limit economic development. Trypanosomes must integrate numerous extracellular signals to be transmitted and cause disease, but the cell surface proteins responsible for these functions are largely unknown. The current proposal aims to identify and study trypanosome surface proteins important for mammalian infection, which will provide better understanding of a critical, yet poorly understood aspect of trypanosome biology and may reveal new therapeutic targets.