Understanding the role of malaria red blood cell binding proteins in invasion and host specificity

了解疟疾红细胞结合蛋白在侵袭和宿主特异性中的作用

• 批准号: 2723209
• 金额: --
• 依托单位: London School of Economics and Political Science
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2723209
• 关键词: Understanding; role; malaria; red; blood

The zoonotic simian malaria parasite P. knowlesi, is a significant and emerging causeof morbidity and mortality in South-East Asia. P. vivax is closely-related, sharesinvasion pathways, and is the second biggest cause of malaria globally. Whilst P. vivaxonly infects humans, P. knowlesi can infect both humans and macaques, and thisprimate reservoir presents an extreme challenge for malaria control. Proteins thatallow the parasite to invade red blood cells (RBCs) are known to be importantdeterminants of virulence and host cell susceptibility, thus critical to understandinghost-range. The project aims to understand the role of the Duffy binding protein (DBP),a malaria parasite protein which is required to bind and invade RBCs. Whilst we knowbinding of DBP to the DARC receptor on human RBCs is essential for invasion of both P.knowlesi (PkDBPa) and P. vivax (PvDBP), we do not know what this binding does, norhow various protein modifications including phosphorylation and proteolytic processingcontribute to its function. We have pioneered orthologue replacement approaches in P.knowlesi to study functions of orthologues from P. vivax- providing a platform todirectly compare how PkDBPa and PvDBP affect invasion and underpin host range. Theproject will dissect the functional role of domains, posttranslational modifications,ligand-receptor interactions comparatively across both Pv and PkDBP using cuttingedgeBar-Seq approaches to study pooled parasite expressing DBP variants (Moon Lab,LSHTM). Structural and biochemical studies will be used to examine how DBPorthologues interact with the DARC receptor (Higgins Lab, Oxford). This will also beinformed by population genetics to understand the extent of polymorphisms in thesekey interacting domains (Campino Lab, LSHTM). Finally, the student will usefluorescent live-cell imaging of invasion to study these processes in real time, gainingnew insights into how these proteins facilitate invasion and define host specificity.

人畜共患的猴疟原虫诺氏疟原虫是东南亚发病率和死亡率的一个重要和新出现的原因。间日疟原虫与疟疾密切相关，它们有共同的入侵途径，是全球疟疾的第二大病因。虽然间日疟原虫只感染人类，但诺氏疟原虫可以感染人类和猕猴，这种灵长类宿主对疟疾控制提出了极大的挑战。已知允许寄生虫侵入红细胞（RBC）的蛋白质是毒力和宿主细胞易感性的重要决定因素，因此对理解鬼范围至关重要。该项目旨在了解达菲结合蛋白（DBP）的作用，这是一种疟疾寄生虫蛋白，需要结合和侵入红细胞。虽然我们知道DBP与人RBC上的DARC受体的结合对于诺氏疟原虫（PkDBPa）和间日疟原虫（PvDBP）的侵袭是必不可少的，但我们不知道这种结合是什么，也不知道各种蛋白质修饰（包括磷酸化和蛋白水解加工）如何有助于其功能。我们在诺氏疟原虫中率先采用了直向同源物替代方法来研究间日疟原虫直向同源物的功能-提供了一个平台来直接比较PkDBPa和PvDBP如何影响入侵和支持宿主范围。该项目将剖析结构域的功能作用，翻译后修饰，配体-受体相互作用比较Pv和PkDBP使用尖端的Bar-Seq方法研究汇集的寄生虫表达DBP变体（月球实验室，LSHTM）。结构和生物化学研究将用于检查DBPorthologues如何与DARC受体相互作用（Higgins Lab，Oxford）。这也将通过群体遗传学来了解这些关键相互作用域中多态性的程度（Campino Lab，LSHTM）。最后，学生将使用荧光活细胞成像的入侵研究这些过程中的真实的时间，获得新的见解，这些蛋白质如何促进入侵和定义宿主特异性。