The aim of the research is to elucidate the biochemical mechanism of entry of the malarial merozoite, Plasmodium falciparum, into the human erythrocyte. The long-term objective of the project is to introduce novel methods to inhibit the merozoite invasion of erythrocytes and thus block the transmission of the parasite at this crucial point in its life-cycle. The following aspects of merozoite invasion will be examined. 1. The mechanism by which the merozoite recognizes and attaches to the erythrocyte surface. 2. The factors that induce erythrocyte membrane deformation and result in the internalization of the merozoite. 3. Erythrocyte membrane and cytoskeletal components involved in membrane invagination; the effect on merozoite invasion of modifications in the organization of these components. In all these studies a merozoite invasion assay will be used which measures directly either the attachment or the invasion of a defined number of isolated merozoites into erythrocytes. Thus, by modifying the surface of merozoites and the surface, membrane and cytoskeletal elements of erythrocytes we will assess the role of various components in the entry. The modifications will include proteolytic cleavage, perturbation of the membrane by crosslinking, lectins, local anaesthetics, cations or ATP. Invasion of merozoites into abnormal erythrocytes, with modified membrane proteins, will also be studied. On the basis of the biochemical results we will attempt to inhibit this interaction with drugs which alter the fluidity of erythrocyte membranes such that they are incapable of internalization of the merozoite.
