Abstract
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.
Highlights
Pathogens constrained to survive within a mammalian host are under evolutionary pressure to acquire mechanisms that favor a chronic infection
VAR2CSA, which is of particular interest for the present study, has previously been identified as the major Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) implicated in Pregnancy-associated malaria (PAM) and shown to interact with chondroitin sulphate A (CSA), non-immune immunoglobulins and possibly other host-receptors, engendering placental sequestration and pathogenesis in PAM [4,5,6,7,8,9]
When following the RNA expression with qPCR over time we found that the transcription of both initially identified var-genes (PFD0630c/PFF0845c) were gradually switched off, with an off-rate of 10.15 and 2.43% per generation, respectively
Summary
Pathogens constrained to survive within a mammalian host are under evolutionary pressure to acquire mechanisms that favor a chronic infection. Asexual Plasmodium falciparum endure by means of antigenic variation Manifestations of this success are the recrudescence of parasites, the occurrence of super-infections, the establishment of chronic asymptomatic infections, and the paucity of sterile immunity. The maintenance of antigen expression is coordinated by the spleen, given that parasites of splenectomized human and animal hosts do not sequester and do not express PfEMP1 on the infected erythrocyte surface [1,2,3]. VAR2CSA, which is of particular interest for the present study, has previously been identified as the major PfEMP1 implicated in PAM and shown to interact with chondroitin sulphate A (CSA), non-immune immunoglobulins and possibly other host-receptors, engendering placental sequestration and pathogenesis in PAM [4,5,6,7,8,9]. How the parasite switches on and off PfEMP1 expression is at present only partly understood
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