Plasmodium falciparum: VAR2CSA expressed during pregnancy-associated malaria is partially resistant to proteolytic cleavage by trypsin

In areas of high Plasmodium falciparum transmission, immunity to malaria is acquired during childhood, so that adults in general are clinically immune. One exception is that first-time pregnant women are susceptible to pregnancy-associated malaria caused by accumulation of parasites in the placenta. Pregnancy-associated variant surface antigens (VSAPAM) mediate binding of the infected erythrocyte to chondroitin sulphate proteoglycans in the placental intervillous space. Several lines of evidence indicate that the molecular identity of VSAPAM is VAR2CSA, a relatively conserved member of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. While native PfEMP1 molecules expressed on the infected erythrocyte surface generally are sensitive to mild trypsinization, some VSAPAM expressing parasite lines are resistant. This finding has led to the suggestion that molecules other than PfEMP1, or at least several different PfEMP1 families mediate the VSAPAM phenotype. To address this issue we incubated three different VAR2CSA expressing parasite lines with trypsin and found that polymorphic VAR2CSA variants can be both protease resistant and sensitive. Trypsin treatment resulted in loss of ability to adhere to CSA and loss of sex-specific antibody recognition of the surface of the infected erythrocyte in one sensitive isolate, whereas CSA binding and sex-specific recognition were largely unaffected by trypsin treatment in two resistant isolates. These results support the hypothesis that VAR2CSA mediates the adhesive and antigenic phenotypes shown by parasites causing placental malaria.