Epigenetic control of antigenic variation in Plasmodium falciparum

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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.