Host-specific cell surface receptors on African trypanosomes

描述(申请人提供)：有鞭毛的原生动物寄生虫布鲁氏锥虫是非洲锥虫病的罪魁祸首，这种疾病在撒哈拉以南非洲造成广泛的人畜死亡和发病。昏睡病如果不治疗是致命的，但目前还没有疫苗存在，而且目前的治疗方法陈旧、有毒且难以管理。因此，迫切需要研究更好地了解这些寄生虫，并促进新的治疗干预措施的开发。布氏毛滴虫在哺乳动物和采采蝇宿主之间交替，必须整合来自外部环境的信号才能在这两种宿主中生存、发育和致病。寄生虫表面蛋白保护宿主的免疫防御，允许获取营养物质，并提供对宿主-寄生虫相互作用和致病重要的感觉和信号功能。因此，细胞表面蛋白对布氏毛滴虫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。到目前为止，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仍然大多未知。这代表着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。通过将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相结合，我们现在能够定义布氏毛滴虫的表面蛋白质组，包括专门用于信号和宿主-寄生虫相互作用的表面亚域。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血液寄生虫中确定布鲁氏毛虫细胞表面的完整蛋白质谱。从这些数据和我们的鞭毛蛋白质组，我们将识别宿主特有的表面蛋白，这些蛋白将被测试对哺乳动物宿主感染的影响。虽然我们的重点是布氏毛滴虫的宿主-寄生虫界面，但我们预计我们的结果将对研究寄生原虫的基础生物学和发病机制的社区产生广泛的兴趣。 与公共卫生相关：非洲锥虫是毁灭性的人类和动物病原体，可导致大量人类死亡并限制经济发展。锥虫必须整合许多细胞外信号才能传递并导致疾病，但负责这些功能的细胞表面蛋白在很大程度上是未知的。目前的建议旨在鉴定和研究对哺乳动物感染重要的锥体表面蛋白，这将有助于更好地了解锥体生物学中一个关键但鲜为人知的方面，并可能揭示新的治疗靶点。

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.