Survival of the Fittest: Another Evolutionary Ploy of the Red Cell to Avoid Malaria Infection

This year is the bicentennial of the birth of Charles Darwin and the sesquicentennial of the publication of On the Origin of Species. For thousands of years the principles of evolution have been played out in the minuet between the malaria parasite and the red blood cell. Survival of the human species has depended upon genetic resistance to malaria across the globe. Evolutionary anti-malarial strategies have included inhibition of intracellular growth, release of mature merozoites or entry into the red cell, promotion of phagocytosis and immune clearance of infected cells, and prevention of vascular or blood cell adherence of infected red cells. Selec­tive pressure has led to high frequencies of otherwise rare RBC genes in certain populations in Africa, Southeast Asia, the Mediterranean, and elsewhere that lessen malarial morbidity and mortality.¹  For example, hemoglobinopathies, includ­ing S, C, E, and thalassemia; metabolic abnormalities, such as glucose-6-phosphate dehydrogenase deficiency; cytoskeletal membrane defects like ovalocytosis or el­liptocytosis; and red cell surface antigens, such as the Duffy blood group system, glycophorins, ABO mol­ecules, and complement receptors, all have been linked to genetic resistance to malaria.^2,3,4 

The life cycle of the Plasmodium falciparum malarial parasite begins when the anopheles mosquito injects sporozoites into a human. These go to the liver where a mature schizont eventually ruptures merozoites into the blood stream where they invade uninfected eryth­rocytes to begin the erythrocytic phase of infection. Infected erythrocyte schizonts can also release mero­zoites (see Figure). Erythrocyte invasion depends on ligands on the merozoite and host receptors on the erythrocyte membrane. An example is the Duffy blood group system and its role in determin­ing susceptibility to Plasmodium vivax infection. Duffy-negative erythrocytes resist invasion of Plasmodium vivax merozoites, and Duffy-negative individuals are hence resistant to infection if exposed to mosquitos infected with Plasmodium vivax.⁵ 

Plasmodium falciparum has a family of genes encoding erythrocyte-binding proteins related to the Duffy-binding proteins of vivax. Several of these have been shown to bind to glycophorins A and C on erythrocytes, but the erythrocyte receptor for one, EBL-1, was not known. Mayer et al., from Louis Miller’s group at Virginia Commonwealth, have now shown that EBL-1 binds glycophorin B.They first showed, by confocal microscopy, that EBL-1 was localized on a Plas­modium falciparum clone Dd/Nm and that it was only expressed in the late schizont phase of infection. EBL-1 could bind to erythrocytes, but this was blocked if the erythrocytes were pre-treated with neuraminidase or chymotrypsin, but not trypsin. The requirement for sialic acid for binding is a characteristic of glycophorin B and indeed glycophorin B-null erythrocytes did not bind EBL-1. When EBL-1 was expressed on CHO cells they acquired capacity to bind glyco­phorin B+ but not glycophorin B-null erythrocytes. Glycophorin B+ cells treated with neuramin­idase and chymotrypsin did not bind EBL-1-expressing CHO cells.