Structural and functional dissection of the molecular machinery responsible for singular antigen expression and immune evasion in African trypanosomes

非洲锥虫中负责单一抗原表达和免疫逃避的分子机制的结构和功能剖析

• 批准号: 2887477
• 金额: --
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2887477
• 关键词: Structural; functional; dissection; molecular; machinery

In the host-pathogen arms race, antigenic variation is one of the most sophisticated virulence mechanisms. Some of the deadliest parasites, like African trypanosomes and malaria parasites, are able to systematically alter the identity of proteins displayed to the host immune system, causing high mortality and morbidity among the world's poorest populations. Trypanosomes are masters of disguise, expressing their variant-surface-glycoprotein in a monogenic fashion from thousands of possible genes - a fine example of extreme biology and a great model system. The pursuit for the machinery responsible for singular-antigen-expression has been a 50-year long quest and had remained elusive in every organism. Its recent identification in trypanosomes ((PMID: 31289266; 33432154) represents a timely opportunity to crack this long-standing mystery. This project aims to:-purify this novel protein complex and solve its tridimensional structure by cryoEM, which will be critical to understand its mechanism of action.-identify key post-translational modifications and characterise their functional/regulatory role. Therefore, the successful applicant will be trained on several cutting-edge technologies, including gene editing (CRISPR/Cas9), mass-spectrometry, next-generation sequencing, protein purification in native conditions and cryoEM. Notably, understanding the molecular mechanisms underpinning antigenic variation is invaluable, as it greatly challenges vaccine development against several organisms.

在宿主 - 病原体武器竞赛中，抗原性变异是最复杂的毒力机制之一。一些最致命的寄生虫，例如非洲锥虫和疟疾寄生虫，能够系统地改变对宿主免疫系统显示的蛋白质的身份，从而在世界上最贫困的人群中导致高死亡率和发病率。锥虫是伪装的大师，以成千上万个可能的基因的单基因方式表达其变体 - 表面 - 糖蛋白 - 极端生物学和出色的模型系统的一个很好的例子。对负责单数抗原表达的机械的追求一直是一个长达50年的追求，并且在每个生物体中仍然难以捉摸。它最近在锥虫中的识别（（PMID：31289266; 33432154）是及时破解这个长期谜团的机会。该项目的目的是： - 促进这种新颖的蛋白质复杂并通过冷冻的态度来解决其三化结构，这将是至关重要的，这将是至关重要的。申请人将接受几种尖端技术的培训，包括基因编辑（CRISPR/CAS9），质谱法，下一代测序，在天然条件下的蛋白质纯化和冷冻，尤其是理解的分子机制是无视抗原变异的。