A restricted subset ofvargenes mediates adherence ofPlasmodium falciparum-infected erythrocytes to brain endothelial cells

Abstract

Cerebral malaria (CM) is a deadly complication of Plasmodium falciparum infection, but specific interactions involved in cerebral homing of infected erythrocytes (IEs) are poorly understood. In this study, P. falciparum-IEs were characterized for binding to primary human brain microvascular endothelial cells (HBMECs). Before selection, CD36 or ICAM-1-binding parasites exhibited punctate binding to a subpopulation of HBMECs and binding was CD36 dependent. Panning of IEs on HBMECs led to a more dispersed binding phenotype and the selection of three var genes, including two that encode the tandem domain cassette 8 (DC8) and were non-CD36 binders. Multiple domains in the DC8 cassette bound to brain endothelium and the cysteine-rich interdomain region 1 inhibited binding of P. falciparum-IEs by 50%, highlighting a key role for the DC8 cassette in cerebral binding. It is mysterious how deadly binding variants are maintained in the parasite population. Clonal parasite lines expressing the two brain-adherent DC8-var genes did not bind to any of the known microvascular receptors, indicating unique receptors are involved in cerebral binding. They could also adhere to brain, lung, dermis, and heart endothelial cells, suggesting cerebral binding variants may have alternative sequestration sites. Furthermore, young African children with CM or nonsevere control cases had antibodies to HBMEC-selected parasites, indicating they had been exposed to related variants during childhood infections. This analysis shows that specific P. falciparum erythrocyte membrane protein 1 types are linked to cerebral binding and suggests a potential mechanism by which individuals may build up immunity to severe disease, in the absence of CM.cytoadhesion | antigenic variation | parasite ligand

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

“…In their companion articles, Avril et al (43) provide independent confirmation of the up-regulation of DC8 genes following selection on brain endothelial cells, and Lavstsen et al (44) show DC8 and DC13 genes to be highly differentially transcribed in patients with severe malaria compared with UM controls, confirming the clinical importance of DC8-and DC13-expressing parasites. DC8 genes were differentially transcribed in all clinical forms of severe malaria (CM, severe malarial anemia, and respiratory distress), consistent with our findings and those of Avril et al (43) that parasites selected for binding to HBEC-5i also could adhere to other primary endothelial cell types, giving the potential to sequester at multiple sites throughout the body in addition to the brain. Taken together, these three studies identify parasites expressing DC8 and DC13 as having high potential for cytoadherence to endothelial cells in the brain and elsewhere and suggest that DC8 and DC13 PfEMP1 variants may be important targets for interventions to treat or prevent severe malaria.…”

Evolutionary structure of Plasmodium falciparum major variant surface antigen genes in South America: Implications for epidemic transmission and surveillance

“…This remarkable biological feature enables P. falciparum to evade the human immune response and establish chronic infections linked to specific cellular interactions. Indeed, Pf EMP1 also binds to host endothelial tissues with different variants exhibiting specific adherence characteristics for tissues, which in turn are associated with distinct disease manifestations (Avril et al., 2012; Claessens et al., 2012; Kraemer & Smith, 2003). Pf EMP1 is thereby considered a virulence factor.…”

Towards an anti-disease malaria vaccine

“…First, the PfEMP1s were arranged into groups A, B and C, depending on their chromosomal location and the domain types encoded [31]. Expression of a subset of PfEMP1s, which contain a specific set of domains, known as CIDRα1 domains, was associated with severe malaria or brain endothelial cell binding [32][33][34][35]. Later, CIDRα1 domains were found to bind to human EPCR [16], thereby preventing EPCR from interacting with its natural ligand, activated protein C [16,36] (Figure 1).…”