ERYTHROCYTE-ENDOTHELIAL INTERACTIONS IN MALARIA

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Malaria, a blood disease of humans, is responsible for over 200 million cases annually, and in Africa alone causes greater than a million deaths. Much effort has been expended to eradicate the disease, but success has remained elusive for a number of reasons: appearance of drug-resistant parasites, the development of vector resistance to insecticides, the absence of an effective vaccine and economic constraints. Infections with Plasmodium falciparum, the most deadly of all the human malarias, are characterized by a marked retention of parasitized erythrocytes in tissue capillaries and venules, a condition called parasite sequestration. The attachment of infected erythrocytes to the vascular endothelium may be an impor- tant cause of the pathology with this parasite since sequestration within the brain blood vessels may produce vasocclusions, impede microvascular blood flow, cause organ infarction and ultimately may result in cerebral malaria. The biological significance and the biochemical mechanisms of erythrocyte endothelial cell adherence are unknown. The present study is designed to identify the molecular factors on the surface of the human erythrocyte and the endothelial cell which are responsible for adhesion thus providing a basis for alternative therapeutic strategies which eventually may be useful in the treatment of cerebral malaria. An in vitro radiometric assay for red cell adhesion has been developed and will be used to assess the effects of fixation, calcium loading, and enzyme treatment on the cytoadherence of infected cells. Isolation of the putative adhesion substance(s) will involve radiolabelling of cells, SDS/ PAGE, immunoprecipitation, Western blotting and construction of cDNA library. The role of the endothelial cell in the adhesion process will be investigated by microfilament disruption, cell fixation, and by determining the effects of the in vitro addition of pharmacologic agents known to affect the inflammatory response.