Abstract
BackgroundMalaria in pregnancy is characterized by accumulation of infected erythrocytes (IE) in the placenta. The key ligand identified as mediating this process is a Plasmodium falciparum erythrocyte membrane protein 1 family member, termed VAR2CSA. VAR2CSA appears to be the main ligand responsible for adhesion to chondroitin sulphate A (CSA). Whether other PfEMP1 molecules can also mediate placental adhesion, independent of CSA binding, is unclear.MethodsThe parasite line CS2 carrying a disrupted var2csa gene (CS2KO) was selected for adhesion to the BeWo choriocarcinoma cell line, which has been proposed as a model for placental malaria. The selected and control IE were tested for adhesion to placental sections and flow cytometry was used to measure recognition of IE by three serum sets from malaria-exposed men and women.ResultsWild-type CS2 adhere to BeWo and placental tissue via CSA. CS2KO IE were successfully selected for adhesion to BeWo, and adhered by a CSA-independent mechanism. They bound to immobilized ICAM-1 and CD36. BeWo-selected CS2KO bound at moderate levels to placental sections, but most binding was to placental villi rather than to the syncytiotrophoblast to which IE adherence occurs in vivo. This binding was inhibited by a blocking antibody to CD36 but not to ICAM-1. As expected, sera from malaria-exposed adults recognized CS2 IE in a gender and parity dependent manner. In one serum set, there was a similar but less pronounced pattern of antibody binding to selected CS2KO IE, but this was not seen in two others. One var gene, It4var19, was particularly abundant in the selected line and was detected as full length transcripts in BeWo-selected IE, but not unselected CS2KO.ConclusionThis study suggests that IE with characteristics similar to the CS2KO have a limited role in the pathogenesis of placental malaria. VAR2CSA appear to be the major ligand for placental adhesion, and could be the basis for a vaccine against pregnancy malaria.
Highlights
Malaria in pregnancy is characterized by accumulation of infected erythrocytes (IE) in the placenta
The accumulation of Plasmodium falciparum-infected erythrocytes (IE) in the maternal placental intervillous space is thought to be mediated by interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of proteins expressed on the IE surface and placental receptors such as chondroitin sulfate A (CSA) and hyaluronic acid (HA) [6,7]
Selection for adhesion of IE to BeWo cells CS2 IE bound at high levels to BeWo cells ((343 ± 54 (SEM) IE/100 BeWo) and, as expected [31], binding was inhibited by more than 70% by free chondroitin sulphate A (CSA) (85 ± 36 IE/100 BeWo)
Summary
Malaria in pregnancy is characterized by accumulation of infected erythrocytes (IE) in the placenta. PAM is characterized by the accumulation of mature stage parasites in the intervillous space of the placenta [4,5]. This sequestration contributes to adverse pregnancy outcomes such as maternal anemia and low birth weight babies [2]. The accumulation of Plasmodium falciparum-infected erythrocytes (IE) in the maternal placental intervillous space is thought to be mediated by interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of proteins expressed on the IE surface and placental receptors such as chondroitin sulfate A (CSA) and hyaluronic acid (HA) [6,7]. PfEMP1 is the dominant parasite derived variant surface antigen (VSA) expressed on IE, and immunity to placental malaria has been correlated with development of immunity to a PfEMP1 molecule, termed VAR2CSA (reviewed in [5])
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