A Unique Virulence Gene Occupies a Principal Position in Immune Evasion by the Malaria Parasite <i>Plasmodium falciparum</i>

<div><p>Mutually exclusive gene expression, whereby only one member of a multi-gene family is selected for activation, is used by the malaria parasite <i>Plasmodium falciparum</i> to escape the human immune system and perpetuate long-term, chronic infections. A family of genes called <i>var</i> encodes the chief antigenic and virulence determinant of <i>P</i>. <i>falciparum</i> malaria. <i>var</i> genes are transcribed in a mutually exclusive manner, with switching between active genes resulting in antigenic variation. While recent work has shed considerable light on the epigenetic basis for <i>var</i> gene activation and silencing, how switching is controlled remains a mystery. In particular, switching seems not to be random, but instead appears to be coordinated to result in timely activation of individual genes leading to sequential waves of antigenically distinct parasite populations. The molecular basis for this apparent coordination is unknown. Here we show that <i>var2csa</i>, an unusual and highly conserved <i>var</i> gene, occupies a unique position within the <i>var</i> gene switching hierarchy. Induction of switching through the destabilization of <i>var</i> specific chromatin using both genetic and chemical methods repeatedly led to the rapid and exclusive activation of <i>var2csa</i>. Additional experiments demonstrated that these represent “true” switching events and not simply de-silencing of the <i>var2csa</i> promoter, and that activation is limited to the unique locus on chromosome 12. Combined with translational repression of <i>var2csa</i> transcripts, frequent “default” switching to this locus and detection of <i>var2csa</i> untranslated transcripts in non-pregnant individuals, these data suggest that <i>var2csa</i> could play a central role in coordinating switching, fulfilling a prediction made by mathematical models derived from population switching patterns. These studies provide the first insights into the mechanisms by which <i>var</i> gene switching is coordinated as well as an example of how a pharmacological agent can disrupt antigenic variation in <i>Plasmodium falciparum</i>.</p>