Fresh isolates from children with severe Plasmodium falciparum malaria bind to multiple receptors

The sequestration of Plasmodium falciparum-infected erythrocytes (pRBC) awa y from the peripheral circulation is a property of all field isolates. Here we have examined the pRBC of 111 fresh clinical isolates from children wit h malaria for a number of adhesive features in order to study their possibl e coexpression and association with severity of disease. A large number of adhesion assays were performed studying rosetting, giant rosetting, and bin ding to CD36, intercellular adhesion molecule 1, platelet endothelial cell adhesion molecule 1, thrombospondin, heparin, blood group A, and immunoglob ulins. Suspension assays were performed at the actual parasitemia of the is olate, while all the static adhesion assays were carried out at an equal ad justed parasitemia. The ability to bind to multiple receptors, as well as t he ability to form rosettes and giant rosettes, was found to be more freque nt among isolates from children with severe versus mild malaria (P = 0.0015 ). Rosettes and giant rosettes were more frequent for children with severe malaria, and the cell aggregates were larger and tighter, than for those wi th mild disease (P = 0.0023). Binding of immunoglobulins (97% of isolates) and of heparin (81% of isolates) to infected erythrocytes was common, and b inding to heparin and blood group A was associated with severity of disease (P = 0.011 and P = 0.031, respectively). These results support the idea th at isolates that bind to multiple receptors are involved in the causation o f severe malaria and that several receptor-ligand interactions work synergi stically in bringing about severe disease.