The membrane characteristics of Plasmodium falciparum‐infected and ‐uninfected heterozygous α⁰thalassaemic erythrocytes

Abstract

Summary. The a thalassaemias are the commonest known human genetic disorders. Although they have almost certainly risen to their current frequencies through natural selection by malaria, the precise mechanism of malaria protection remains unknown. We have investigated the characteristics of red blood cells (RBCs) from individuals heterozygous for a 0 thalassaemia (-/aa) from a range of perspectives. On the basis of the hypothesis that defects in membrane transport could be relevant to the mechanism of malaria protection, we investigated sodium and potassium transport and the activity of the Plamodium falciparuminduced choline channel but found no significant differences in -/aa RBCs. Using flow cytometry, we found that thalassaemic P. falciparum-infected RBCs (IRBCs) bound 44% more antibody from immune plasma than control IRBCs. This excess binding was abrogated by predigestion of IRBCs with trypsin but was not directed at the variant surface molecule PfEMP1. Furthermore, we found no evidence for altered cytoadhesion of a-thalassaemic IRBCs to the endothelial receptors intercellular adhesion molecule-1 (ICAM-1), CD36 or thrombospondin. We hypothesize that altered red-cell membrane band 3 protein may be a target for enhanced antibody binding to a-thalassaemic IRBCs and could be involved in the mechanism of malaria protection.

α-Thalassemia Impairs the Cytoadherence of Plasmodium falciparum-Infected Erythrocytes

“…Specifically, α-thalassemia is not associated with reduced parasite prevalence [5], [6], [7] or densities in vivo as determined by examining blood smears from children with asymptomatic parasitemia [2], [8], uncomplicated malaria [2], [3], [4], [5], [6], [7], [9], [10], [11], [12], or severe malaria [2], [13]. As noted by other investigators [3], [5], [14], these observations indicate that α-thalassemia does not protect against severe malaria by mechanisms that impair the ability of parasites to invade or develop within RBCs [15], [16], or promote the removal of parasitized RBCs from the bloodstream by increased neoantigen expression [15], [17] or increased antibody binding [18]. Indeed, we have observed extremely high parasite burdens (up to 200,000/µl) in some −α/αα and −α/−α children with malaria (unpublished data).…”

An Immune Basis for Malaria Protection by the Sickle Cell Trait

“…falciparum has been demonstrated in vitro [24], a process that appears to be mediated by a mechanism essentially similar to that involved in the phagocytosis of senescent or damaged normal erythrocytes. Experimental data suggest that this process is initiated by enhanced oxidant damage to the erythrocyte membrane and that this leads to the aggregation of band 3 protein and the binding of autologous IgG and complement [24], a mechanism similar to that previously proposed for α thalassaemia [25]. It therefore seems plausible that enhanced immunity could be mediated by the accelerated acquisition of antibodies to altered host antigens expressed on the parasite-infected red cell surface, such as band 3 protein [26].…”

The Effect of α +-Thalassaemia on the Incidence of Malaria and Other Diseases in Children Living on the Coast of Kenya

“…The enhanced expression of antigens on the surface of late-stage P. falciparum-infected red blood cells that has been identified in a number of studies [ 53, 54], may provide an alternative mechanism—by resulting in their early or enhanced removal from circulation. However, we would anticipate that if this were the mechanism, it would be reflected in reduced parasite densities as are seen in participants with an HbAS genotype [ 12].…”