Antigenic variation is a subtle process of fundamental importance to the survival of a microbial pathogen. In Plasmodium falciparum malaria, PfEMP1 is the major variable antigen and adhesin expressed at the surface of the infected erythrocyte, which is encoded for by members of a family of 60 var-genes. Peri-nuclear repositioning and epigenetic mechanisms control their mono-allelic expression. The switching of PfEMP1 depends in part on variable transition rates and short-lived immune responses to shared minor epitopes. Here we show var-genes to switch to a common gene that is highly transcribed, but sparsely translated into PfEMP1 and not expressed at the erythrocyte surface. Highly clonal and adhesive P. falciparum, which expressed distinct var-genes and the corresponding PfEMP1s at onset, were propagated without enrichment or panning. The parasites successively and spontaneously switched to transcribe a shared var-gene (var2csa) matched by the loss of PfEMP1 surface expression and host cell-binding. The var2csa gene repositioned in the peri-nuclear area upon activation, away from the telomeric clusters and heterochromatin to transcribe spliced, full-length RNA. Despite abundant transcripts, the level of intracellular PfEMP1 was low suggesting post-transcriptional mechanisms to partake in protein expression. In vivo, off-switching and translational repression may constitute one pathway, among others, coordinating PfEMP1 expression.

Plasmodium falciparum being the most lethal plasmodiae is still a major cause of the disease burden and mortality in malaria endemic areas. Due to the wide spread drug resistance in combination with poor socio-economic situation in the vast majority of the endemic countries, malaria is today a great global challenge. The scientific community is, however, progressing. The 23 Mb genome of P. falciparum has been decoded and publicly available. Data of transcriptional profiling at certain developmental stages have already been generated. More than 50% of P. falciparum genes are transcribed constitutively in all the developmental stages of parasite life cycle. Functional disruption of these genes might have implications for parasite growth and development. Available microarray data indicate that P. falciparum preferentially expresses rif and stevor gene families at gametocyte and sporozoite stages while var genes are predominantly expressed at the erythrocytic stage. Gene regulation mechanisms of the variant gene families in P. falciparum are still not understood though some regulatory elements have been proposed. The occurrence of severe malaria is determined by both parasite and human host factors. Sequestration and antigenic variation are two of the evasion mechanisms utilized by P. falciparum in order to escape the human host defences. Understanding the molecular mechanisms underlying these phenomena is of a major importance and interest in malaria research. Here, we summarize and highlight the recent progress in molecular aspects of severe malaria.

No abstract