Characterization of hemoglobin C and other variant hemoglobin erythrocytes and their protective mechanism against severe malaria

Malaria, caused by the Plasmodium falciparum parasite, causes roughly two million deaths per year. This high mortality, over thousands of years, is thought to have resulted in the natural selection of numerous hemoglobin variants that protect against severe disease. Although epidemiological studies have proven this protection for a number of variants, the mechanism by which they protect remains unclear. Hemoglobin C (HbC) differs from normal hemoglobin by having a lysine for glutamate substitution at the sixth amino acid in beta globin. HbC is found in West Africa where it has been shown to protect against severe malaria. In this thesis, I will characterize HbC erythrocytes, with emphasis on their removal from circulation and describe the mechanism by which HbC protects against severe malaria. In the first chapter, I show that HbC erythrocytes have a number of characteristics that they share with aged normal erythrocytes yet are not removed from the circulation. This is likely due to the fact that opsonins found in HbC erythrocyte membrane extracts are internalized and are therefore not recognized as markers for erythrocyte removal. In the second chapter, I show that HbC protects against malaria by reducing and altering the display of an important parasite protein on the surface of an infected erythrocyte. This probably results in a reduction in sequestration and the pathologic immune reaction typically seen in severe malaria. Finally, in the third chapter I show that other hemoglobin variant erythrocytes share some of these altered characteristics and that they too probably protect against severe malaria by altering the parasite antigen's quantity and display. Therefore, this mechanism of protection appears likely to be a universal one for all variant hemoglobin erythrocytes and is probably dependent on their altered membrane characteristics.