Optimization and inhibition of the adherent ability of Plasmodium falciparum-infected erythrocytes.
The vast majority of the 1-2 million malaria associated deaths that occur each year are due to anemia and cerebral malaria (the attachment of erythrocytes containing mature forms of Plasmodium falciparum to the endothelial cells that line the vascular beds of the brain). A "model system" for the study of cerebral malaria employs amelanotic melanoma cells as the "target" cells in an in vitro cytoadherence assay. Using this model system we determined that the optimum pH for adherence is 6.6 to 6.8, that high concentrations of Ca2+ (50mM) result in increased levels of binding, and that the type of buffer used influences adherence (Bis Tris > MOPS > HEPES > PIPES). We also observed that the ability of infected erythrocytes to cytoadhere varied from (erythrocyte) donor to donor. We have produced murine monoclonal antibodies against P. falciparum-infected red cells which recognize modified forms of human band 3; these inhibit the adherence of infected erythrocytes to melanoma cells in a dose-responsive fashion. Antimalarials (chloroquine, quinacrine, mefloquine, artemisinin), on the other hand, affected adherence in an indirect fashion i.e. since cytoadherence is due, in part, to the presence of knobs on the surface of the infected erythrocyte, and knob formation is dependent on intracellular parasite growth, when plasmodial development is inhibited so is knob production, and consequently adherence is ablated.
Department of Biology, University of California, Riverside 92521.
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Smith
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Crandall
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Prudhomme
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IW
Sherman
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000913:Antibodies, Protozoan / Q000276:immunology; D000962:Antimalarials / Q000494:pharmacology; D002021:Buffers; D002118:Calcium / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D003470:Culture Media / Q000494:pharmacology; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016778:Malaria, Falciparum / Q000097:blood / Q000469:parasitology*; D008545:Melanoma / Q000473:pathology; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000913:Antibodies, Protozoan; D000962:Antimalarials; D002021:Buffers; D003470:Culture Media; D002118:Calcium