Structural studies of the clustering of PfEMP1 proteins on the surface of Plasmodium falciparum-infected erythrocytes

恶性疟原虫感染红细胞表面 PfEMP1 蛋白聚集的结构研究

• 批准号: G0901062/2
• 负责人: Matthew Higgins
• 金额: $ 45.35万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0901062%2F2
• 关键词: Structural; studies; clustering; PfEMP1; proteins

Malaria is one of the most devastating diseases that affect humanity. It kills about 2 million people each year and causes about 500 million serious cases. The disease is caused by tiny parasites, known as Plasmodium. The deadly symptoms of the disease, including fever, anaemia and even coma and death, occur during the blood phase of the parasite life cycle. Here, the parasites invade red blood cells and live and divide within them, using the red cells for protection from the immune system and as a source of nutrients to fuel parasite replication. After invasion the parasites remodel red cells, causing dramatic changes that make them a suitable home. One of these changes is the formation of structures called knobs on the red cell surface. Sticky proteins, known as PfEMP1 proteins, become clustered at these knobs. These sticky proteins interact with different molecules on the blood vessel surfaces or with human tissues such as brain or placenta. They also cause red blood cells to stick together to form tiny clumps known as rosettes. By sticking throughout the body, the infected red cells hide from detection, allowing the parasite to grow and divide in peace and prolonging the infection. But this stickiness also causes some of the most severe symptoms of the disease. When infected red cells and rosettes become clustered in the brain, blood flow is disrupted, leading to cerebral malaria and causing coma and death. The accumulation of infected red cells on the placenta is also deadly, causing the severe symptoms of malaria during pregnancy.We are studying the molecules that the parasite uses to cause the formation of knobs and to cause adhesive proteins to cluster at these knobs. We will focus on proteins called KAHRP, spectrin and PfEMP1. The parasite protein, KAHRP, interacts with the red cell protein, spectrin, and acts as the major scaffold for knob formation. PfEMP1 proteins can then interact with KAHRP, causing them to become clustered at the knobs. We will use a variety of techniques to study the precise structural details of how these three proteins interact with one another. By understanding how knobs are formed, and how PfEMP1 proteins are clustered, we aim to provide information that will guide the development of medicines to prevent knob formation or the development of stickiness. These treatments will be useful to prevent many of the most deadly symptoms of malaria.

疟疾是影响人类的最毁灭性疾病之一。它每年杀死约200万人，并造成约5亿个严重案件。该疾病是由小寄生虫（称为疟原虫）引起的。该疾病的致命症状，包括发烧，贫血甚至昏迷和死亡，发生在寄生虫生命周期的血液阶段。在这里，寄生虫侵入红细胞并在其中生活和分裂，使用红细胞保护免疫系统，并作为营养物质来促进寄生虫复制的来源。入侵后，寄生虫重塑了红细胞，从而引起巨大的变化，使其成为合适的家。这些变化之一是在红细胞表面上形成称为旋钮的结构。粘性蛋白，称为PFEMP1蛋白，在这些旋钮上聚集。这些粘性蛋白与血管表面上的不同分子或人体组织（例如脑或胎盘）相互作用。它们还会导致红细胞粘在一起形成称为玫瑰花结的细小团块。通过粘在整个身体中，被感染的红细胞躲藏起来，使寄生虫在和平中生长和分裂并延长感染。但是这种粘性也会引起该疾病中一些最严重的症状。当感染的红细胞和玫瑰花结聚集在大脑中时，血液流动会破坏，导致脑疟疾并引起昏迷和死亡。感染红细胞在胎盘上的积累也是致命的，导致怀孕期间的严重疟疾症状。我们正在研究寄生虫用来引起旋钮形成的分子，并在这些旋钮下凝聚在这些旋钮上。我们将专注于称为KAHRP，SPECTRIN和PFEMP1的蛋白质。寄生虫蛋白KAHRP与红细胞蛋白，光谱蛋白相互作用，并充当旋钮形成的主要支架。然后，PFEMP1蛋白可以与KAHRP相互作用，从而导致它们在旋钮上聚集。我们将使用各种技术来研究这三种蛋白质如何相互作用的精确结构细节。通过了解如何形成旋钮以及如何聚类PFEMP1蛋白，我们旨在提供指导药物开发以防止旋钮形成或发育粘性的信息。这些治疗方法对于预防许多最致命的疟疾症状将很有用。