Research
Characterization of VAR2CSA-deficient Plasmodium falciparum-infected erythrocytes selected for adhesion to the BeWo placental cell line
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* Corresponding author: Stephen J Rogerson sroger@unimelb.edu.au
1 Department of Medicine, University of Melbourne (RMH/WH), Post Office Royal Melbourne Hospital, Parkville VIC 3050, Australia
2 Infectious Diseases and Immunology Division, Queensland Institute of Medical Research, QLD, Australia
3 Australian Centre for International and Tropical Health, a joint program of the QIMR and the School of Population Health, University of Queensland, Brisbane, QLD, Australia
4 The Nossal Institute for Global Health, University of Melbourne, Parkville VIC, Australia
5 The Walter and Eliza Hall Institute of Medical Research, Parkville VIC, Australia
Malaria Journal 2008, 7:51 doi:10.1186/1475-2875-7-51
Published: 26 March 2008Abstract
Background
Malaria 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.
Methods
The 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.
Results
Wild-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.
Conclusion
This 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.