The Role of PfEMP1 Expression and Immunity in Ugandian Children with Severe Malaria

Abstract

Severe malaria, primarily caused by Plasmodium falciparum infection, is among the leading causes of childhood mortality globally. A key virulence factor and source of antigenic variation and immune evasion during infection is P. falciparum erythrocyte membrane protein 1 (PfEMP1). Encoded for by approximately 60 var genes, this complex protein mediates cytoadherence of infected erythrocytes to the host endothelium and is a prominent immune target for the anti-malarial immune response in children. During severe malaria, specific domains of PfEMP1 that bind to endothelial protein C receptor (EPCR) and intercellular adhesion molecule-1 (ICAM-1) on host endothelial cells, are more prevalently expressed. The interaction of these proteins and infected erythrocytes mediates the sequestration of infected erythrocytes and plays a role in severe malaria pathogenesis. Antibodies to these domains develop over time with exposure to the parasite and are thought to contribute to immunity against severe malaria in children. In this study, whole blood samples from children with different forms of severe malaria, enrolled in two observational prospective cohort studies were used to quantify the expression of PfEMP1 domains using RT-qPCR and to measure the antibody response to PfEMP1 domains via a bead-based multiplex immunoassay. Using these samples, we demonstrated that although the expression of var transcripts encoding PfEMP1 domains was generally similar across children with different forms of severe malaria, the expression of variants encoding specific EPCR-binding domains was associated with thrombocytopenia and severe anemia. The antibody response to PfEMP1 domains in children with severe malaria was highest in children with SMA and children with asymptomatic parasitemia, but not associated with decreased risk of additional malaria episodes. Overall, the results of this study suggest that PfEMP1 is acting similarly across different forms of severe malaria but that it can be related to pathogenesis and severe malaria immunity.