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Background: Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates parasite sequestration in postcapillary venules in P. falciparum malaria. PfEMP1 types can be classified based on their cysteine-rich interdomain region (CIDR) domains. Antibodies to different PfEMP1 types develop gradually after repeated infections as children age, and antibodies to specific CIDR types may confer protection. Methods: Levels of immunoglobulin G to 35 recombinant CIDR domains were measured by means of Luminex assay in acute-stage (baseline) and convalescent-stage plasma samples from Papua New Guinean children with severe or uncomplicated malaria and in healthy age-matched community controls. Results: At baseline, antibody levels were similar across the 3 groups. After infection, children with severe malaria had higher antibody levels than those with uncomplicated malaria against the endothelial protein C receptor (EPCR) binding CIDRalpha1 domains, and this difference was largely confined to older children. Antibodies to EPCR-binding domains increased from presentation to follow-up in severe malaria, but not in uncomplicated malaria. Conclusions: The acquisition of antibodies against EPCR-binding CIDRalpha1 domains of PfEMP1 after a severe malaria episode suggest that EPCR-binding PfEMP1 may have a role in the pathogenesis of severe malaria in Papua New Guinea.