Abstract
BackgroundA subset of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1SM) is involved in the cytoadherence of P. falciparum-infected red blood cells (iRBC) contributing to the pathogenesis of severe disease among young children in malaria endemic areas. The PfEMP1SM are encoded by group A var genes that are composed of a more constrained range of amino acid sequences than groups B and C var genes encoding PfEMP1UM associated with uncomplicated malaria. Also, unlike var genes from groups B and C, those from group A do not have sequences consistent with CD36 binding – a major cytoadhesion phenotype of P. falciparum isolates.MethodsA 3D7 PfEMP1SM sub-line (3D7SM) expressing VAR4 (PFD1235w/MAL8P1.207) was selected for binding to CD36. The protein expression of this parasite line was monitored by surface staining of iRBC using VAR4-specific antibodies. The serological phenotype of the 3D7SM parasites was determined by flow cytometry using malaria semi-immune and immune plasma and transcription of the 59 var genes in 3D7 were analysed by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) using var-specific primers.ResultsA selection-induced increased adhesion of 3D7SM iRBC to CD36 resulted in a reduced var4 transcription and VAR4 surface expression.ConclusionVAR4 is not involved in CD36 adhesion. The current findings are consistent with the notion that CD36 adhesion is not associated with particular virulent parasite phenotypes, such as those believed to be exhibited by VAR4 expressing parasites.
Highlights
A subset of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1SM) is involved in the cytoadherence of P. falciparum-infected red blood cells contributing to the pathogenesis of severe disease among young children in malaria endemic areas
Reduced expression of VAR4 following selection for CD36 binding To determine the effect of CD36 selection on VAR4 surface expression, mouse or rabbit antibodies against the CIDR1α domain of VAR4 were used to stain three 3D7 sub-lines – 3D7 expressing PfEMP1UM (3D7UM), 3D7 PfEMP1SM sub-line (3D7SM)-CD36 and 3D7SM-drift and the parasite protein surface expression subsequently analysed by flow cytometry (Figure 1A)
A previous study has shown that var4, a group A var gene, is highly transcribed and surface expressed in 3D7 parasites expressing PfEMP1SM (3D7SM) compared to 3D7 expressing PfEMP1UM (3D7UM), suggesting an association between VAR4 and severe malaria [28]
Summary
A subset of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1SM) is involved in the cytoadherence of P. falciparum-infected red blood cells (iRBC) contributing to the pathogenesis of severe disease among young children in malaria endemic areas. The dominant serological phenotype (recognition by semi-immune and immune human plasma) changes to PfEMP1SM following selection of 3D7 using DynaBeads coated with IgG from semi-immune children [27]. This 3D7SM shows transcriptional upregulation and protein surface expression of one particular group A var gene, var (PFD1235w/ MAL8P1.207)[28]. Group A var genes, together with certain other B/A type were found to be transcribed in isolates from children with cerebral malaria, but not from isolates from highly parasitaemic patients without severe malaria syndromes [29]
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