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

疟疾是影响人类的最具破坏性的疾病之一。它每年造成约200万人死亡，并造成约5亿起严重病例。这种疾病是由微小的寄生虫引起的，这种寄生虫被称为疟疾。这种疾病的致命症状，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期。在这里，寄生虫入侵红细胞并在其中生活和分裂，利用红细胞来保护免疫系统，并作为营养来源来促进寄生虫的复制。在入侵后，寄生虫重塑红细胞，造成戏剧性的变化，使它们成为合适的家园。这些变化之一是在红细胞表面形成了称为旋钮的结构。粘性蛋白，即PfEMP1蛋白，聚集在这些节处。这些粘性蛋白质与血管表面的不同分子相互作用，或者与大脑或胎盘等人体组织相互作用。它们还会使红细胞粘连在一起，形成被称为玫瑰花环的小团块。通过粘在全身，受感染的红细胞隐藏起来，使寄生虫能够和平地生长和分裂，从而延长感染时间。但这种粘性也会导致这种疾病的一些最严重的症状。当受感染的红细胞和玫瑰花结聚集在大脑中时，血液流动被扰乱，导致脑型疟疾，并导致昏迷和死亡。感染的红细胞在胎盘上的聚集也是致命的，会导致怀孕期间疟疾的严重症状。我们正在研究这种寄生虫用来导致结节形成的分子，并使黏附蛋白聚集在这些结节上。我们将重点研究称为Kahrp、Spectrin和PfEMP1的蛋白质。寄生虫蛋白kahrp与红血球蛋白Spectrin相互作用，是形成结节的主要支架。然后，PfEMP1蛋白可以与kahrp相互作用，导致它们在节处聚集。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。通过了解结节是如何形成的，以及PfEMP1蛋白是如何聚集的，我们的目标是提供信息，指导药物的开发，以防止结节的形成或粘性的发展。这些治疗方法将有助于预防疟疾的许多最致命的症状。

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.