A structured transcriptional switching network that coordinates antigenic variation by malaria parasites

项目总结/摘要 恶性疟原虫是导致最严重的人类疟疾的病原体， 这种疾病每年导致40多万人死亡，其中大多数是非洲的儿童。这些原生动物 寄生虫侵入并最终破坏其宿主的循环红细胞（RBC），导致严重的 贫血以及脑型疟疾和妊娠相关疟疾的频繁致死综合征。超过 在感染过程中，出现了小的寄生虫亚群，它们具有改变的抗原性， 表型，从而避免宿主的抗体应答。这一过程被称为抗原性 变异，并负责疾病的持续性以及寄生虫血症的波 常见于恶性疟原虫感染。恶性疟原虫感染红细胞的抗原变异结果 来自多拷贝var基因家族的个体成员之间的表达开关。每个var基因 编码一种不同形式的蛋白质PfEMP 1。这种蛋白质被放置在受感染的红细胞表面 并介导粘附于在血管壁的内皮表面上发现的特异性受体， 被感染的个体。这种粘连是造成许多感染的疾病表现的原因 与恶性疟原虫感染，包括脑型疟疾和妊娠相关疟疾。只有一个变量 基因在某一时刻被任何给定的寄生虫表达，因此决定了寄生虫的抗原表型， 感染的细胞以及它们的粘附特性。因此，var基因表达是两者的核心。 抗原变异和疟疾感染的毒力。该项目的长期目标是 了解调节var基因表达和抗原变异的分子机制， 疟原虫近年来的重要工作已经定义了许多维持一种生物学特性的分子方面。 基因处于活跃或沉默状态，然而，控制转录之间切换的机制 活性基因仍然完全不确定。此外，考虑到感染可能包括数十亿人， 寄生虫，他们似乎如何协调开关事件，以限制激活到一个单一的或少量的 基因是完全未知的。相比之下，不协调的随机切换会迅速 耗尽了所有的无功功率没有证据表明寄生虫之间有交流， 在var基因家族中似乎没有严格的转换顺序，因此这是如何 完成的事情仍然是完全神秘的。该项目的具体目标是破译 这一现象的机械基础。目的1研究一个不寻常的，高度保守的变异的作用 一个似乎起着协调转换事件的中央组织基因作用的基因。目标2将 确定寄生虫如何感知胎盘的存在并改变var基因表达， 这个不寻常的利基优势。这一项目将有助于目前正在进行的努力， 抗原变异，从而缩短感染的时间并降低其严重性。

Project Summary/Abstract Plasmodium falciparum is the causative agent responsible for the most severe form of human malaria, a disease that kills more than 400,000 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 infected RBC surface 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 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. Significant work in recent years has defined many molecular aspects that maintain a gene in the active or silent state, however the mechanisms governing switching between transcriptionally active genes remain entirely undefined. Moreover, given that an infection can include billions of individual parasites, how they seemingly coordinate switching events to limit activation to a single or small number of genes at a time is completely unexplored. In contrast, uncoordinated, random switching would rapidly exhaust the entire var repertoire. There is no evidence of communication between parasites, and there does not appear to be a strict switching order within the var gene family, therefore how this is accomplished remains completely mysterious. The specific aims of the project are designed to decipher the mechanistic basis of this phenomenon. Aim 1 investigates the role of an unusual, highly conserved var gene that appears to function as central organizing gene that coordinates switching events. Aim 2 will determine how parasites sense the presence of a placenta and alter var gene expression to take advantage of this unusual niche. This project will contribute to the ongoing effort to disrupt the process of antigenic variation and thereby shorten the length of an infection and reduce its severity.