Mechanistic insights into coordinated var transcriptional switching in malaria parasites

The exceptional virulence of the human malaria parasite, Plasmodium falciparum, is attributed to the adhesive properties of infected red blood cells and the parasite's ability to avoid antibody recognition through antigenic variation. Both properties are derived from the hypervariable surface protein PfEMP1, which is encoded by members of the multi-copy var gene family. Waves of parasitemia during an infection are thought to correspond to var transcriptional switching, enabling parasites to avoid elimination by antibodies targeting previously expressed forms of PfEMP1. The mechanisms underlying and regulating var transcriptional switching remain incompletely understood. Here, we show how transient activation of the var2csa locus mediates var switching, while the expression of non-coding RNAs from this locus contributes to repression of var2csa transcription and affects var switching frequencies. Furthermore, we find that an upstream open reading frame in the 5'-untranslated region of the var2csa transcript destabilizes the var2csa mRNA through the induction of the nonsense-mediated RNA decay pathway. This process promotes transcriptional activation of an alternative var gene. Our findings provide molecular insights into the coordinated transcriptional switching of the var gene family, which contributes to chronic infection.