var Gene Regulation and Antigenic Variation in Malaria

 描述(申请人提供)：恶性疟原虫是人类最严重的疟疾的病原体，这种疾病每年导致80多万人死亡，其中大部分是非洲的幼儿。这些原生动物寄生虫入侵并最终破坏其宿主的循环红细胞(RBC)，导致严重贫血以及经常致命的脑型疟疾和妊娠疟疾综合征。在感染过程中，出现具有改变抗原表型的小亚群寄生虫，从而避免宿主的抗体反应。这一过程被称为抗原变异，是该病的持续性以及在恶性疟原虫感染中经常观察到的寄生虫血症波动的原因。恶性疟原虫感染红细胞的抗原性变异是由于多拷贝var基因家族成员之间表达的转换所致。每个var基因编码一种不同形式的蛋白质，称为PfEMP1。这种蛋白被放置在受感染的红细胞表面，并介导与感染者血管壁内皮细胞表面上发现的特定受体的黏附。这种粘附性是感染恶性疟原虫的许多疾病表现的原因，包括脑型疟疾和妊娠疟疾。任何给定的寄生虫一次只表达一个var基因，因此决定了感染细胞的抗原表型和它们的粘附性。因此，var基因的表达是疟疾感染的抗原变异和毒力的核心。该项目的长期目标是了解疟疾寄生虫调节var基因表达和抗原变异的分子机制。以前的工作发现了在所有var基因中发现的一个独特的调控元件，它是正确调控每个var基因所必需的。该项目的具体目标是准确地确定该元件如何对基因家族产生影响，以及如何协调var基因之间的切换。目的1研究在非编码RNA的转录过程中，通过与RNA polII的直接相互作用，特异性的组蛋白修饰物PfSET2与var基因的招募。第二个目的是研究一种不寻常的var基因在协调转换过程中的作用。总体而言，该项目将有助于正在进行的努力，以开发扰乱抗原变异过程的方法，从而缩短感染的时间并降低其严重性。

 DESCRIPTION (provided by applicant): Plasmodium falciparum is the causative agent responsible for the most severe form of human malaria, a disease that kills more than 800,000 people a year, mostly young children in Africa. These protozoan parasites invade and ultimately destroy circulating red blood cells (RBCs) of their host, leading to severe anemia and the frequently lethal syndromes of cerebral malaria and pregnancy associated malaria. Over the course of an infection, small sub-populations of parasites arise that have an altered antigenic phenotype, thus avoiding the antibody response of the host. This process is referred to as antigenic variation and is responsible for the persistent nature of the disease as well as the waves of parasitemia frequently observed in P. falciparum infections. Antigenic variation of P. falciparum infected RBCs results from switches in expression between individual members of the multi-copy var gene family. Each var gene encodes a different form of a protein called PfEMP1. This protein is placed on the surface of the infected RBCs and mediates adhesion to specific receptors found on the endothelial surfaces of the blood vessel walls of the infected individual. This adhesion is responsible for many of the disease manifestations of infection with P. falciparum, including both cerebral malaria and pregnancy associated malaria. Only a single var gene is expressed at a time by any given parasite, thus determining the both the antigenic phenotype of the infected cells as well as their adhesive properties. Therefore var gene expression is at the heart of both antigenic variation and virulence of malaria infections. The long-term objectives of this project are to understand the molecular mechanisms that regulate var gene expression and antigenic variation by malaria parasites. Previous work identified a unique regulatory element found in all var genes that is necessary for proper regulation of each var gene. The specific aims of the project are designed to determine exactly how this element exerts its influence on the gene family and how switching between var genes is coordinated. Aim 1 investigates the recruitment of a specific histone modifier called PfSET2 to var genes through direct interactions with RNA pol II during the transcription of noncoding RNAs. The second aim investigates the role of an unusual var gene in coordinating the switching process. Collectively, this project will contribute to the ongoing effort to develop methods to disrupt the process of antigenic variation and thereby shorten the length of an infection and reduce its severity.