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MALARIA: Obstacles and Opportunities
Plasmodium species can invade by binding to one of several erythrocyte receptors, a multivalent vaccine will be required to completely inhibit merozoite invasion of red blood cells.
Rhoptries and micronemes are organelles located near the anterior end of the merozoite. Release of the contents of these organelles is essential to erythrocyte invasion, and there is evidence this process is susceptible to antibody attack (Holder and Freeman, 1984).
Antibodies from immune individuals can bind to the surface of merozoites as they are released from schizont-infected erythrocytes, forming large merozoite clusters incapable of invading erythrocytes (Chulay et al., 1981). Antibodies dissociated from these immune complexes have been used to identify the antigens involved (Chulay et al., 1987; Lyon et al., 1989). These include integral membrane proteins present on the merozoite surface as well as proteins that are only loosely associated with the merozoite surface.
Erythrocyte Surface Antigens Antigens on the surface of infected erythrocytes are a particularly attractive target for vaccine intervention because of the long period during which they are exposed to the immune system. In P. falciparum, some of these antigens mediate the adherence of infected erythrocytcs to endothelium, which causes mature-stage erythrocytic parasites to become sequestered in blood capillaries, where they are able to avoid destruction by the spleen (Howard et al., 1990).
Erythrocytes parasitized by mature P. falciparum in vitro can adhere to at least three different host endothelial cell molecules: CD-36, thrombospondin, and ICAM-1 (CD-54) (Howard and Gilladoga, 1989; Chulay and Ockenhouse, 1990). Parasitized erythrocytes can also adhere to (rosette with) normal erythrocytes, another type of cell-to-cell interaction (Udomsangpetch et al., 1989). The parasite molecules responsible for adherence have not been completely identified, but it appears that at least one is a high molecular weight (250 to 300 kilodaltons) variable antigen called P. falciparum erythrocyte membrane protein 1 (Leech et al., 1984; Howard et al., 1990). This protein has multiple distinct serotypes and may also undergo true antigenic variation. There is evidence that partially immune adults develop antibodies able to recognize epitopes that are conserved among all serotypes (Marsh and Howard, 1986).
Antigens Crucial to Parasite Growth Monoclonal or polyclonal antibodies have been added to in vitro culture systems and screened to identify those that inhibit parasite growth (Perrin et al., 1981; Saul et al., 1984, 1985; Schofield et al., 1986; Lew et al., 1989). Protection of animals by passive transfer of these antibodies can confirm their value. The antigens recognized by such inhibitory antibodies are of obvious interest.