title: Default Pathway of var2csa switching and translational repression in Plasmodium falciparum.
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.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Bobo W
authors.initials: BW
authors.lastname: Mok
authors.forename: Ulf
authors.initials: U
authors.lastname: Ribacke
authors.forename: Niloofar
authors.initials: N
authors.lastname: Rasti
authors.forename: Fred
authors.initials: F
authors.lastname: Kironde
authors.forename: Qijun
authors.initials: Q
authors.lastname: Chen
authors.forename: Peter
authors.initials: P
authors.lastname: Nilsson
authors.forename: Mats
authors.initials: M
authors.lastname: Wahlgren
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000096:biosynthesis* / Q000235:genetics*; D002448:Cell Adhesion; D002467:Cell Nucleus / Q000378:metabolism; D002999:Clone Cells; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005812:Genes, Switch; D016678:Genome; D015151:Immunoblotting; D017404:In Situ Hybridization, Fluorescence; D009363:Neoplasm Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010963:Plasmodium falciparum / Q000166:cytology / Q000235:genetics*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000953:Antigens, Protozoan; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C512601:VAR2CSA protein, Plasmodium falciparum; C097051:epithelial membrane protein-1