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: G0901062/1
• 负责人: Matthew Higgins
• 金额: $ 46.77万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0901062%2F1
• 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具破坏性的疾病之一。它每年导致约200万人死亡，并导致约5亿例严重病例。这种疾病是由被称为疟原虫的微小寄生虫引起的。该病的致命症状，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，在其中生存和分裂，利用红细胞保护免疫系统，并作为营养来源，为寄生虫的复制提供动力。在入侵后，寄生虫重塑了红细胞，引起了巨大的变化，使它们成为一个合适的家园。其中一种变化是红细胞表面形成一种叫做“旋钮”的结构。被称为PfEMP1的粘性蛋白质聚集在这些旋钮上。这些粘性蛋白质与血管表面的不同分子或与大脑或胎盘等人体组织相互作用。它们还会使红细胞粘在一起，形成被称为玫瑰花的小块。通过粘在全身，受感染的红细胞隐藏起来不被发现，允许寄生虫在和平中生长和分裂，延长感染时间。但这种粘性也会导致一些最严重的疾病症状。当受感染的红细胞和玫瑰花聚集在大脑中时，血液流动就会中断，导致脑疟疾，并导致昏迷和死亡。受感染的红细胞在胎盘上的积累也是致命的，在怀孕期间引起严重的疟疾症状。我们正在研究寄生虫用来形成旋钮并使黏附蛋白聚集在这些旋钮上的分子。我们将重点关注KAHRP， spectrin和PfEMP1蛋白。寄生虫蛋白KAHRP与红细胞蛋白spectrin相互作用，并作为旋钮形成的主要支架。然后，PfEMP1蛋白可以与KAHRP相互作用，导致它们聚集在旋钮上。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。通过了解旋钮是如何形成的，以及PfEMP1蛋白是如何聚集的，我们的目标是提供指导药物开发的信息，以防止旋钮的形成或粘性的发展。这些治疗方法将有助于预防许多最致命的疟疾症状。