In 1986, the human morbidity and mortality due to malaria was estimated to be nearly a half-billion cases. Of these > 50% were due to one species, Plasmodium falciparum, and > 2.3 million were fatal. The increase in numbers of malaria infections, and the worldwide spread of the disease, is due to the appearance of parasites resistant to the Inexpensive antimalarial drug chloroquine, the development of mosquito resistance to insecticides, the absence of an effective vaccine, and economic constraints. The most severe complication of Infections with P. falciparum is cerebral malaria. In sub-Saharan Africa more than a million children die of this condition. The precise mechanisms that underlie cerebral malaria are unknown. Currently, the most favored explanation is the """"""""mechanical"""""""" hypothesis: blood flow through the brain is impeded by the adherence of parasitized red cells to the postcapillary venular endothelium by a specific interaction between adhesive molecules present on surface protuberances (knobs) of the malaria-infected erythrocyte and an endothelial receptor. Adhesion may also involve thrombospondin, CD36 antigen, ICAM-1, decreased deformability of the parasitized red cell, and modulation of the adhesive properties of the endothelial cell. The present study is designed to identify and characterize those molecular factors on the surfaces of the malaria-infected erythrocyte and the endothelial cell that are responsible for adhesion, and as such, could provide a basis for alternative therapeutic strategies for the treatment of cerebral malaria. To study the adhesin of the P. falciparum-infected red cell, monoclonal antibodies against several cytoadherent lines will be prepared, and the surface antigen identified by immunofluorescence, immunoprecipitation, and inhibition of adhesion. The gene for the parasite-encoded adhesin will be cloned, and/or adhesin expression associated with red cell membrane proteins determined. The effect of pro- and anti-inflammatory agents on umbilical vein and brain endothelial cell (EC) adhesion will be studied in vitro; the EC receptor will be identified, and characterized using techniques similar to those described for the adhesins on the malaria-infected red cell.
