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Multiple var gene transcripts are expressed in Plasmodium falciparum infected erythrocytes selected for adhesion
R Noviyanti1, G V Brown, M E Wickham
1Infection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia.
Abstract:
Adherence of Plasmodium falciparum-infected erythrocytes to the post-capillary endothelium is an important characteristic of malaria infection. The adhesion is mediated predominantly by P. falciparum Erythrocyte Membrane Protein-1 (PfEMP1), a clonally variant protein expressed on the surface of infected red blood cells that appears to be a target of protective immunity. A multi-membered var gene family encodes PfEMP1 and switching expression of different var genes conveys different antigenic and adhesive properties to infected red blood cells. Knowledge about transcriptional control of phenotypic expression, or the mechanisms that allow multiple binding specificities, is very limited. Here, we describe a series of phenotypic selection experiments, which resulted in the expression of different PfEMP1 and the detection of multiple full-length var gene transcripts in the mature trophozoite stage. However, a dominant form of PfEMP1 appeared to be expressed, which suggested that most var transcripts do not lead to a surface expressed PfEMP1 molecule. Parasites bound to specific receptors still expressed multiple full-length var genes and mature trophozoites selected for increased adhesion to a specific receptor retained the ability to bind to multiple receptors. Our findings suggest that a defined adhesive phenotype can be associated with expression of multiple var genes.
Insights
Malaria parasites express multiple surface proteins (PfEMP1) from var genes, but typically display only one. This study shows that even when binding to specific receptors, parasites can express multiple var genes, suggesting complex adhesion regulation.
Area of Science:
- Malaria pathogenesis
- Molecular parasitology
- Immunology
Background:
- Plasmodium falciparum malaria pathogenesis involves infected erythrocyte adhesion to endothelium.
- P. falciparum Erythrocyte Membrane Protein-1 (PfEMP1), encoded by var genes, mediates this adhesion and is a target of immunity.
- Mechanisms controlling var gene expression and PfEMP1's multiple binding specificities are poorly understood.
Purpose of the Study:
- To investigate the transcriptional control of var gene expression and PfEMP1 phenotypic variation.
- To understand how parasites achieve multiple binding specificities during malaria infection.
Main Methods:
- Phenotypic selection experiments were performed on P. falciparum cultures.
- Detection of full-length var gene transcripts in mature trophozoites.
- Analysis of PfEMP1 expression and parasite binding to specific receptors.
Main Results:
- Phenotypic selection led to expression of different PfEMP1 variants and detection of multiple var gene transcripts.
- A dominant PfEMP1 form was often expressed, suggesting post-transcriptional regulation.
- Parasites selected for specific receptor binding still expressed multiple var genes and retained multi-receptor binding ability.
Conclusions:
- A single adhesive phenotype in malaria may be associated with the expression of multiple var genes.
- Var gene expression and PfEMP1 display are complex, involving post-transcriptional control.
- Malaria parasites exhibit flexibility in adhesion despite selection for specific phenotypes.