Epigenetic control of antigenic variation in Plasmodium falciparum

疟疾是一个巨大的全球健康问题，每年导致数百万人死亡。人类只有在多年反复感染后存活下来，才会对疟疾产生部分免疫力。发展对疟疾的免疫力的很大困难在于病原体恶性疟原虫不断改变其表面涂层特性的能力。寄生虫通过一种称为抗原变异的过程来实现这种免疫逃避。基因相同的寄生虫可以表达不同的表面涂层，并且对这一过程的控制是在遗传控制水平之上叠加的。这个系统被称为表观遗传控制。表观遗传控制包括调控机制，如基因在寄生虫内部的包装方式，以及对包裹基因的蛋白质（称为组蛋白）的化学修饰。我们希望了解寄生虫用来协调抗原变异现象的表观遗传控制系统。我们将使用两种方法来获得这种理解；第一种是基因筛选，利用跳跃DNA（称为转座子）在寄生虫中产生突变，从而破坏抗原变异背后的控制机制。鉴定突变基因将向我们展示哪些基因在正常寄生虫中组织抗原变异。我们的第二种方法是基因敲除寄生虫基因，这些基因与其他更容易理解的生物（如人类和酵母）中控制表观遗传机制的基因相关。我们将测试这些靶向基因缺失的影响，以发现这些基因中哪些参与调节抗原变异。从这些发现中获得的见解将提高我们对疟疾寄生虫如何逃避我们免疫系统的理解。更好地了解这种免疫逃避可能有助于我们了解如何制造更好的疟疾疫苗。

Malaria is an enormous global health problem that kills millions of people each year. Humans develop only partial immunity to malaria only if they survive many years of repeated infection. Much of the difficulty in developing immunity to malaria lies in the ability of the causative agent, Plasmodium falciparum, to continually change the properties of its surface coat. The parasite achieves this immune evasion through a process called antigenic variation. Genetically identical parasites can express different surface coats, and the control of this process is superimposed above the level of genetic control. This system is referred to as epigenetic control. Epigenetic control includes regulatory mechanisms such as the way that genes are packed inside the parasite, and chemical modifications to the proteins (called histones) around which genes are wrapped. We wish to understand the epigenetic control system that the parasite uses to orchestrate the phenomenon of antigenic variation. We will use two methods to gain this understanding; the first is a genetic screen that will create mutations in the parasite using jumping DNA (called transposons) that will break down the control mechanism behind antigenic variation. Identifying the mutated genes will show us which genes organize antigenic variation in normal parasites. Our second approach is to genetically knockout parasite genes that are related to the genes that govern epigenetic mechanisms in other, better understood organisms like humans and yeast. We will test the effect of these targeted gene deletions to discover which of these genes are involved in regulating antigenic variation. The insights gained from these discoveries will improve our understanding of how the malaria parasite evades our immune system. A better understanding of this immune evasion may help us to understand how to build better vaccines against malaria.