Genetics of antigenic variation in Plasmodium falciparum

Abstract

Malaria caused by the protozoan parasite Plasmodium falciparum is characterized by long-term, persistent infections that can last for many months. The ability of this parasite to avoid clearance by the human immune system is dependent on its capacity to continuously alter the surface exposed antigenic proteins that that are vulnerable to antibody recognition and attack, a process called antigenic variation. Significant work in recent years has contributed to our understanding of the mechanisms underlying this process, including the genes encoding the antigenic proteins and the DNA sequence elements that control their expression. In addition, the epigenetic "marks" that are associated with activation and silencing of individual genes have been extensively characterized. These studies have led to a model that includes multiple layers of regulation that ultimately lead to the tight coordination of expression of the genes responsible for antigenic variation by malaria parasites. Here we review some more recent data that adds additional complexity to our understanding of these regulatory layers.

Figure 1

Three layers of var gene regulation. A. The conserved structure of var genes and their putative regulatory elements are shown. The transcription start site (TSS) of the mRNA and the “sterile” transcripts are shown with bent arrows. The sterile transcripts are derived from both DNA strands and are shown as green wavy lines. The orange box upstream of the TSS represents regulatory elements mapped by deletion analysis or EMSA. The uORF found in the UpsE promoter of var2csa (red box) functions as a translational repressor. B. Modifications to the structure of chromatin surrounding var genes are shown. Condensed, silent chromatin (left) is characterized by tightly packed nucleosomes carrying the H3K9me3 modification while the nucleosomes found in loose, transcriptionally active chromatin surrounding “on” var genes (right) are marked by H3K4me3, H3K4me2 and H3K9ac histone modifications. C. The hypothetical structure of nuclei from P. falciparum. Regions containing condensed heterochromatin (green) are found at the nuclear periphery while euchromatin is found in the internal regions (grey). Clusters of silent var genes (red) are thought to be tethered to the nuclear membrane. The active var locus (green) relocates to a specific region of euchromatin near the nuclear membrane which may represent a specific var gene expression site.