Invasion of Erythrocytes by Malaria Parasites: a Cellular and Molecular Overview

Studies on the morphology, cell biology, and immunology of invasion have characterized events that are now being studied at the molecular level. The initial events of invasion are receptor-specific. A determinant associated with Duffy blood group antigens is involved in the invasion of human erythrocytes by P. knowlesi and P. vivax. The Duffy Fya antigen has recently been identified and further characterization of its role in reception and invasion should now be possible. P. falciparum utilizes erythrocyte ligands that differ from those of P. knowlesi and P. vivax. Sialic acid and a trypsin-sensitive erythrocyte membrane component are important for invasion by P. falciparum parasites. There is evidence that at least two ligands are involved in invasion. For P. knowlesi there is a ligand for attachment, common to both Duffy-negative and Duffy-positive human erythrocytes, and a second ligand for invasion, which is found only on Duffy-positive human erythrocytes. P. vivax also appears to utilize two ligands, a Duffy-associated ligand and a ligand specific for reticulocytes. P. falciparum binds to sialic acid-dependent and sialic acid-independent trypsin-sensitive ligands. P. falciparum merozoites require erythrocyte sialic acid to varying degrees in order to invade; this indicates heterogeneity of the receptor mechanism. Monoclonal antibodies and recombinant DNA technology have greatly facilitated the identification, isolation, and characterization of proteins that may be involved in invasion. Molecules that may have invasion-related functions include those whose antibodies block invasion, those that bind to erythrocyte ligands important for invasion, those that appear on the merozoite surface, and those that appear to be inserted into the erythrocyte membrane at the time of invasion. It has not been possible to identify a definite function for any of the molecules identified thus far. No monoclonal or polyclonal monospecific antibody has been identified that reacts specifically over the surface of the apical region of the merozoite where junction formation occurs. Identification of molecules responsible for apical attachment and junction formation will be important for our understanding of invasion. In terms of vaccine development, it is not yet known whether any of the molecules discussed here will prove to be effective immunogens. It is clear from the data obtained with the 140-kd protein of P. knowlesi that antigenic variation poses a potential problem for vaccine development. As the molecular events responsible for invasion become better understood, novel ways may be devised to interfere with the process and prevent the disease.