The human malaria parasite <i>Plasmodium falciparum</i> can sense environmental changes and respond by antigenic switching.

Abstract

The primary antigenic and virulence determinant of the human malaria parasite <i>Plasmodium</i> <i>falciparum</i> is a variant surface protein called PfEMP1. Different forms of PfEMP1 are encoded by a multicopy gene family called <i>var</i>, and switching between active genes enables the parasites to evade the antibody response of their human hosts. <i>var</i> gene switching is key for the maintenance of chronic infections; however, what controls switching is unknown, although it has been suggested to occur at a constant frequency with little or no environmental influence. <i>var</i> gene transcription is controlled epigenetically through the activity of histone methyltransferases (HMTs). Studies in model systems have shown that metabolism and epigenetic control of gene expression are linked through the availability of intracellular S-adenosylmethionine (SAM), the principal methyl donor in biological methylation modifications, which can fluctuate based on nutrient availability. To determine whether environmental conditions and changes in metabolism can influence <i>var</i> gene expression, <i>P</i>. <i>falciparum</i> was cultured in media with altered concentrations of nutrients involved in SAM metabolism. We found that conditions that influence lipid metabolism induce <i>var</i> gene switching, indicating that parasites can respond to changes in their environment by altering <i>var</i> gene expression patterns. Genetic modifications that directly modified expression of the enzymes that control SAM levels similarly led to profound changes in <i>var</i> gene expression, confirming that changes in SAM availability modulate <i>var</i> gene switching. These observations directly challenge the paradigm that antigenic variation in <i>P. falciparum</i> follows an intrinsic, programed switching rate, which operates independently of any external stimuli.