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

“非洲锥体表面暴露的不变表位的电子计算机靶标识别，用于设计和开发新的免疫疗法”-旧标题寄生虫表面的景观：非洲锥体表面暴露的不变表位的特征，作为新免疫疗法的假定靶标-新标题非洲锥体表面暴露的不变表位的计算机靶标识别，用于设计和开发新的免疫疗法。成功的感染和传播依赖于锥虫检测、相互作用和适应环境的能力。作为细胞外寄生虫，锥虫细胞表面作为寄生虫与其外部环境之间的分子接口，在营养获取、信号传递以及对抗宿主的先天性和获得性免疫攻击方面发挥着重要作用。主要的表面蛋白是变异型表面糖蛋白(VSG)，它的特性很好，在宿主免疫逃避中发挥着重要作用。通过VSG的屏蔽，非变异表面蛋白在很大程度上避免了宿主免疫系统的检测。然而，这些蛋白质中的一些蛋白质的功能需要它们突出VSG层。这一要求在寄生虫的武器装备中提供了一个潜在的弱点。抗体-药物结合物是一种越来越多的肿瘤免疫疗法。我们最近已经证明，抗体-药物结合物可以通过一种非变异的表面蛋白靶向锥虫细胞表面，并在体外和体内有效地杀死寄生虫。该博士项目将使用电子结构建模方法来预测寄生虫细胞表面暴露的表位，并确定这些表位应该在多大程度上可用于免疫疗法。然后，我们将对这些预测进行实验评估。这将作为电子靶标识别方法的模型系统，为合理设计和开发新型免疫疗法提供一般的模型，并提供对寄生虫细胞表面景观的全面分析。该项目将主要在布里斯托尔大学生物科学学院，由Paula MacGregor博士和Fabio Parmegiani博士指导，但也将在Andrea Gonzalez-Munoz博士的监督下，在剑桥格兰特公园的阿斯利康实习。请联系Paula MacGregor进行非正式查询(paula.macgregor@bristol.ac.uk)。对计算生物学感兴趣将是有利的。主要参考文献：MacLeod，OJ.S.等人，2020。非洲锥虫受体利用宿主因子H传递给采采子载体。自然通讯，11(1)：1326。MacGregor，P.等人，2019。单剂抗体-药物结合物可治愈非洲锥虫病的1期模型。《公共科学图书馆·被忽视的热带疾病》，13(5)：e0007373。Schwede，A.等人，2015年。非洲锥虫血液的VSG外壳是如何与外部蛋白质相互作用的？PLOS病原体，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.