The role of Plasmodium falciparum var genes in malaria in pregnancy

Abstract

Sequestration of Plasmodium falciparum-infected erythrocytes in the placenta is responsible for many of the harmful effects of malaria during pregnancy. Sequestration occurs as a result of parasite adhesion molecules expressed on the surface of infected erythrocytes binding to host receptors in the placenta such as chondroitin sulphate A (CSA). Identification of the parasite ligand(s) responsible for placental adhesion could lead to the development of a vaccine to induce antibodies to prevent placental sequestration. Such a vaccine would reduce the maternal anaemia and infant deaths that are associated with malaria in pregnancy. Current research indicates that the parasite ligands mediating placental adhesion may be members of the P. falciparum variant surface antigen family PfEMP1, encoded by var genes. Two relatively well-conserved subfamilies of var genes have been implicated in placental adhesion, however, their role remains controversial. This review examines the evidence for and against the involvement of var genes in placental adhesion, and considers whether the most appropriate vaccine candidates have yet been identified.

Fig. 1

Plasmodium falciparum var gene structure and repertoires. A. Schematic diagram of a typical P. falciparum var gene. DBL, Duffy Binding-Like domain; CIDR, cysteine-rich interdomain region; TM, transmembrane region; ATS, acidic terminal segment. B. Different P. falciparum lines have distinct var gene repertoires with little overlap, except for a small number of well-conserved var gene sub-families. The var gene repertoire is represented as a pile of stacked boxes. The full sequence of all var genes is only known for the 3D7 parasite clone (and its parental line NF54).

Fig. 2

Transcription of a specific var gene is upregulated in a P. falciparum clone selected for binding to a particular host receptor. The entire var gene repertoire of approximately 50–60 var genes from the IT/FCR3 parasite line is represented as stacked boxes. Unselected parasites tend to express a variety of different var genes. In a parasite clone derived from IT/FCR3 selected for high levels of rosetting (R29), the transcription of the R29R + var1 gene is upregulated in comparison to isogenic non-rosetting parasites (Rowe et al., 1997). Similarly, a parasite clone selected for high levels of ICAM-1 binding upregulates a different var gene, A4tresvar(Smith et al., 2000a). Heterologous expression studies showed that the PfEMP1 variant encoded by R29R + var1 binds RBC, while that encoded by A4tresvar binds ICAM-1 (Rowe et al., 1997; Smith et al., 2000a). This pattern of upregulation of a single specific var gene in a parasite clone selected for adhesion to a particular receptor has been widely demonstrated, although the transcriptional control mechanisms responsible for regulation of var gene expression are not well understood. In contrast, at least one var gene, FCR3varCSA, has many unusual features. It is well-conserved and widely transcribed among different parasite isolates/lines and its transcription is not associated with a particular adhesion phenotype (Kyes et al., 2003).

Fig. 3

Schematic diagram showing the extra-cellular domains of three P. falciparum var genes that have been implicated in CSA-binding. The CSA-binding regions demonstrated by heterologous expression and in vitro adhesion assays (Buffet et al., 1999; Reeder et al., 2000) are shown as purple blocks.