Authors

Y Azasi¹; G Lindergard¹; A Ghumra¹; J A Rowe¹;  ¹ Centre for Immunity, Infection and Evolution, Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh

Discussion

Marked sequestration of P. falciparum infected erythrocytes (IEs) in the brain is a unique pathology of cerebral malaria. The parasites express variant surface antigen, var genes which is thought to enable IEs to sequester by binding to host cells to avoid splenic clearance. Var genes encode PfEMP1, a >200kDa protein expressed on the surface of IEs made up of N-terminal segment, DBL and CIDR domains, implicated as the ligand for sequestration. Studies have shown that var types DC8 and 13 are predominantly transcribed by cerebral malaria isolates compared to uncomplicated malaria isolates and these same DC8 and 13 expressing IEs bind to human brain endothelial cells (HBEC). We therefore set out to make recombinant proteins and antibodies to DC8 and 13 PfEMP1 domains of three parasite lines expressing variants HB3var03, IT4var07 and IT4var19 that bind HBEC-5i, to determine which domain(s) was mediating adhesion. We show that with the exception of adhesion of the EPCR-binding strain, IT4var19 which was inhibited by CIDRα1 domains of all three parasites, the NTS.DBLα, DBLβ and CIDRα1 recombinant proteins tested had no effect on adhesion of both homologous and heterologous strains.  These data suggest other regions of PfEMP1 and or multiple domains may be involved in cytoadhesion and also show that the EPCR-CIDRα1 interaction is not sufficient for binding of all DC8 and 13 expressing parasite lines hence different receptors may be involved.