A molecular switch in the efficiency of translation reinitiation controls expression of var2csa, a gene implicated in pregnancy-associated malaria.

Plasmodium falciparum malaria parasites export the protein PfEMP1 to the surface of infected erythrocytes, enabling them to adhere to receptors in the microvasculature and thereby avoid clearance by the spleen. The gene var2csa encodes the form of PfEMP1 that binds specifically within the placenta, causing pregnancy-associated malaria, and appears to not be expressed in the absence of a placenta. We previously described an upstream open reading frame (uORF) that is responsible for repression of translation of the downstream ORF (dORF) that encodes VAR2CSA, thus keeping the gene silent when parasites infect non-pregnant individuals. To elucidate the molecular mechanism by which this repression is overcome during pregnancy, we stably transformed parasites with reporter gene constructs designed to detect switches in the efficiency of dORF translation. We found that proper regulation of switching relies on two separate components, (i) active translation of the uORF and (ii) sequence-specific characteristics of the surrounding transcript, which together control the ability of the ribosome complex to reinitiate a second round of translation and thus express VAR2CSA. These results provide the first details of a molecular switch that allows parasites take advantage of the unique niche provided by the placenta.