PFEMP1, POLYMORPHISM AND PATHOGENESIS

The virulence of Plasmodium falciparum relative to the other species o f malarial parasite which infect humans is thought to be due both to t his parasite's ability to adhere to endothelial cells lining small blo od vessels and, in some cases, to its ability to form rosetres with un infected erythrocytes. The latter phenotype has been found more freque ntly in cases of severe disease. The former property means that only t he younger, asexual, intra-erythrocytic forms circulate whereas the mo re mature developmental stages are sequestered in the vasculature of a variety of organs. When large numbers of parasites accumulate in a vu lnerable target organ such as the brain, then the life-threatening con dition of cerebral malaria may result. While the factors that control whether or not cerebral malaria develops are not clearly defined, one crucial determinant mag be the endothelial receptors utilised by the i nfecting isolate. Many such receptors have been identified, including CD36, thrombospondin, ICAM-1, VCAM, E-selectin and chondroitin-4-sulph ate. The results of laboratory, field, post-mortem and direct receptor -binding studies indicate that, of the receptors currently identified, ICAM-1 binding is most likely to be associated with the development o f cerebral malaria. The molecule expressed on the surface of the infec ted erythrocyte which mediates adherence to endothelium belongs to a l arge family of clonally variable antigens encoded by the var genes. Th e evidence for this conclusion and progress in defining the regions of var-gene products responsible for receptor-specific binding are discu ssed. Finally, the organization of the nai genes within and between pa rasites is discussed in relation to the evolution of the var-gene fami ly and its functions of antigenic variation and endothelial adhesion.