Abstract
Malaria, caused by the parasite Plasmodium falciparum, is responsible for substantial morbidity, mortality and economic losses in tropical regions of the world. Pregnant women are exceptionally vulnerable to severe consequences of the infection, due to the specific adhesion of parasite-infected erythrocytes in the placenta. This adhesion is mediated by a unique variant of PfEMP1, a parasite encoded, hyper-variable antigen placed on the surface of infected cells. This variant, called VAR2CSA, binds to chondroitin sulfate A on syncytiotrophoblasts in the intervillous space of placentas. VAR2CSA appears to only be expressed in the presence of a placenta, suggesting that its expression is actively repressed in men, children or non-pregnant women; however, the mechanism of repression is not understood. Using cultured parasite lines and reporter gene constructs, we show that the gene encoding VAR2CSA contains a small upstream open reading frame that acts to repress translation of the resulting mRNA, revealing a novel form of gene regulation in malaria parasites. The mechanism underlying this translational repression is reversible, allowing high levels of protein translation upon selection, thus potentially enabling parasites to upregulate expression of this variant antigen in the presence of the appropriate host tissue.
Highlights
Adults living in areas endemic for Plasmodium falciparum malaria acquire partial immunity through repeated infections
Expression of a single gene called var2csa has been linked to targeting of the placenta, and this gene represents a key element in the virulence of P. falciparum infections
We describe an upstream open reading frame–mediated mechanism used by parasites to repress translation of var2csa mRNA, providing a mechanism for controlling gene expression at the level of protein translation
Summary
Adults living in areas endemic for Plasmodium falciparum malaria acquire partial immunity through repeated infections. This immunity is suddenly lost with the onset of a first pregnancy, resulting in frequent occurrence of pregnancy associated malaria (PAM), a form of the disease which endangers both the mother and the fetus [1]. Red blood cells infected with P. falciparum adhere to various host receptors in the vasculature in order to avoid clearance by the spleen [3], and this adherence causes several distinct disease syndromes, most notably cerebral malaria resulting from adherence of parasites in the brain. Binding to the syncytiotrophoblasts of the placenta results in massive sequestration of infected erythrocytes (IEs) in this organ [5]
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