Plasmodium falciparum Variant Surface Antigen Expression Patterns during Malaria

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Abstract
The variant surface antigens expressed on Plasmodium falciparum–infected erythrocytes are potentially important targets of immunity to malaria and are encoded, at least in part, by a family of var genes, about 60 of which are present within every parasite genome. Here we use semi-conserved regions within short var gene sequence “tags” to make direct comparisons of var gene expression in 12 clinical parasite isolates from Kenyan children. A total of 1,746 var clones were sequenced from genomic and cDNA and assigned to one of six sequence groups using specific sequence features. The results show the following. (1) The relative numbers of genomic clones falling in each of the sequence groups was similar between parasite isolates and corresponded well with the numbers of genes found in the genome of a single, fully sequenced parasite isolate. In contrast, the relative numbers of cDNA clones falling in each group varied considerably between isolates. (2) Expression of sequences belonging to a relatively conserved group was negatively associated with the repertoire of variant surface antigen antibodies carried by the infected child at the time of disease, whereas expression of sequences belonging to another group was associated with the parasite “rosetting” phenotype, a well established virulence determinant. Our results suggest that information on the state of the host–parasite relationship in vivo can be provided by measurements of the differential expression of different var groups, and need only be defined by short stretches of sequence data. Hope that it will be possible to develop a malaria vaccine is supported by the fact that individuals who have grown up in malaria endemic regions learn to carry malarial infections without suffering disease. Surprisingly little is still known about how this immunity develops. Much current research focuses on how the host develops immune responses to parasite antigens that are exposed to the host immune system. A major family of such antigens are inserted into the surface of parasite-infected erythrocytes, where they undergo antigenic switching to evade a developing antibody response. These proteins are encoded by a family of approximately 60 var genes, variants of which are present in every parasite genome. The extreme diversity of the var genes has prevented meaningful comparison of their expression in clinical isolates. However, the authors of this paper show that var genes can be placed in groups that have a similar representation in the genomes of all parasites that the authors collected from Kenyan children. Having demonstrated an underlying similarity at the genomic level, the authors show that the var expression patterns vary markedly between different patients. The expression levels of specific groups of var genes was associated with poorly developed antibody responses in the children and a well-established parasite virulence phenotype. The study provides tools for exploring how host and parasite adapt to one another as immunity develops.