The landscape of a parasite surface: Characterisation of the exposed invariant epitopes on the surface of African trypanosomes as putative targets of

“非洲锥虫表面暴露不变表位的计算机目标识别，用于设计和开发新型免疫治疗药物”-旧标题寄生虫表面的景观：非洲锥虫表面暴露的不变表位作为新型免疫治疗剂的假定靶点的表征-新标题In-非洲锥虫表面暴露的不变表位的硅靶鉴定用于新型免疫治疗剂的设计和开发。撒哈拉非洲。成功的感染和传播依赖于锥虫检测、相互作用和适应其环境的能力。作为细胞外寄生虫，锥虫细胞表面充当寄生虫与其外部环境之间的分子界面，并在营养获取、信号传导和对抗宿主先天性和适应性免疫攻击中起作用。主要的表面蛋白，变异表面糖蛋白（VSG），已被很好地表征，并在宿主免疫逃避中发挥重要作用。通过VSG的屏蔽，非变异表面蛋白在很大程度上被保护免于宿主免疫系统的检测。然而，这些蛋白质中的一些的功能需要它们突出到VSG层之外。抗体-药物偶联物是一种日益增多的肿瘤免疫治疗药物。我们最近已经表明，抗体-药物缀合物可以通过非变体表面蛋白靶向锥虫细胞表面，并在体外和体内有效杀死寄生虫。这个博士项目将使用计算机结构建模方法来预测寄生虫细胞表面暴露的表位，并确定这些表位在多大程度上可以用于免疫治疗。然后我们将通过实验来评估这些预测。这将作为一个模型系统，用于计算机目标识别方法，用于合理设计和开发新型免疫治疗药物，并提供对寄生虫细胞表面景观的全面分析。该奖学金将主要设在布里斯托大学生物科学学院，由Paula MacGregor博士和Fabio Parmeggiani博士监督，但将包括在AstraZeneca，Grant Park，剑桥的Andrea Gonzalez-Munoz博士监督下的职位。请联系Paula MacGregor进行非正式查询（paula. bristol.ac.uk）。对计算生物学感兴趣将是有利的。主要参考文献：麦克劳德，O.J.S.，例如，2020.一种非洲锥虫受体利用宿主因子H传播给采采蝇媒介。《自然通讯》，11（1）：1326。MacGregor，P.，等，2019.单剂量的抗体-药物缀合物治愈非洲锥虫病的1期模型。PLOS被忽视的热带病，13（5）：e0007373。Schwede，A.，等，2015.非洲锥虫的VSG外壳如何与外部蛋白质相互作用？PLOS Pathogens，11（12）：e1005259。

"In-silico target identification of the exposed invariant epitopes on the surface of African trypanosomes for the design and development of novelimmunotherapeutics" - old titleThe landscape of a parasite surface: Characterisation of the exposed invariant epitopes on the surface of African trypanosomes as putative targets of novel immunotherapeutics - new titleIn-silico target identification of the exposed invariant epitopes on the surface of African trypanosomes for the design and development of novel immunotherapeutics.Several trypanosome species are pathogens of humans and livestock in sub-Saharan Africa. Successful infection and transmission rely on the ability of the trypanosome to detect, interact with, and adapt to its environment. As extracellular parasites, the trypanosome cell surface acts as the molecular interface between the parasite and its external environment and functions in nutrient acquisition, signalling, and countering host innate and adaptive immune attack. The major surface protein, the Variant Surface Glycoprotein (VSG), has been well characterised and plays important roles in host immune evasion. The non-variant surface proteins are largely protected from detection by the host immune system through shielding by the VSG. However, the functions of some of these proteins necessitate that they protrude out of the VSG layer. This requirement provides a potential weakness in the parasite's armoury.Antibody-drug conjugates are an increasing class of oncological immunotherapeutics. We have recently shown that antibody-drug conjugates can be targeted to the trypanosome cell surface through a non-variant surface protein and lead to efficient killing of the parasite in vitro and in vivo. This PhD project will use in silico structural modelling methods to predict exposed epitopes at the parasite cell surface and determine to what degree these should be accessible to immunotherapeutics. We will then assess those predictions experimentally. This will serve as a model system for in silico target identification methods for the rational design and development of novel immunotherapeutics for in general and provide a comprehensive analysis of the parasite cell surface landscape. This studentship will be primarily based in the School of Biological Sciences at the University of Bristol under the supervision of Dr Paula MacGregor and Dr Fabio Parmeggiani, but will include placements at AstraZeneca, Grant Park, Cambridge under the supervision of Dr Andrea Gonzalez-Munoz. Please contact Paula MacGregor for informal enquiries (paula.macgregor@bristol.ac.uk). An interest in computational biology would be advantageous. Key references: Macleod, O.J.S., et al., 2020. An African trypanosome receptor exploits host factor H for transmission to the tsetse vector. Nature Communications, 11(1): 1326. MacGregor, P., et al., 2019. A single dose of antibody-drug conjugate cures a stage 1 model of African trypanosomiasis. PLOS Neglected Tropical Diseases, 13(5): e0007373. Schwede, A., et al., 2015. How does the VSG coat of bloodstream form African trypanosomes interact with external proteins? PLOS Pathogens, 11(12): e1005259.