The aetiological agent responsible for the most severe form of human malaria is the intraerythrocytic protozoan parasite plasmodium falciparum. Clinical manifestations of P. falciparum malaria include cerebral malaria, which is the major cause of death from this disease, whereby infected erythrocytes sequester in the deep vascular beds of the brain. During growth of the asexual stage of the parasite in human erythrocytes, a series of dramatic and extensive changes occur in the structural and functional properties of the infected erythrocyte, which includes development of knob structures and the ability to adhere to endothelium. Crucial to these changes are proteins of parasite origin which are either deposited on the inner aspect of erythrocyte membrane or inserted into it. Several parasite proteins are present at the cytoplasmic side of the knob structure including the knob-associated histidine rich protein (KAHRP) and PfEMP3. The adhesive properties of P. falciparum infected red cells are due to the antigenically variant parasite protein PfEMP1 which is concentrated in the knob on the outside of the membrane. It is likely that interaction of the cytoplasmic tail of PfEMP1 with other proteins and the cytoskeleton of the red blood cell are crucial to the strength of the adhesive interactions of the parasite-infected red cell with ligands on endothelial cells. The hypothesis to be tested, in this work, is that both KAHRP and PfEMP3 are important for the expression of the adhesive properties encoded by PfEMP1 on the P.falciparum infected red cell surface. This will be done by constructing targeted gene disruptions of KAHRP and PfEMP3 as well as introducing mutated genes to determine the effect on the adhesive and membrane properties of the parasite infected red cell. This will enable an understanding of the role of these proteins and their relationship with PfEMP1 in determining the adhesive properties of the infected red cell. These studies will contribute to an increased understanding of the pathophysiology of falciparum malaria. In the broader sense, our findings in red blood cells (the simplest and best understood of all eukaryotic cells) may be useful to augment our understanding of the role of particular proteins in the regulation of cell structure and the mechanical and adhesive properties of eukaryotic cells in general.
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