Rigid membranes of Malayan ovalocytes: a likely genetic barrier against malaria

Abstract

A high frequency of nonhemolytic hereditary ovalocytosis in Malayan aborigines is thought to result from reduced susceptibility of affected individuals to malaria. Indeed, Kidson et al. recently showed that ovalocytes from Melanesians in Papua New Guinea are resistant to infection in culture by the malarial parasite Plasmodium falciparum. In order to determine if protection against parasitic invasion in these ovalocytes might be the result of some altered membrane material property in these unusual cells, we measured their membrane and cellular deformability characteristics using an ektacytometer . Ovalocytic red cells were found to be much less deformable in comparison to normal discoid red cells. Similar measurements on isolated membrane preparations revealed a marked reduction in ovalocytic membrane deformability. To produce equal deformation of ovalocytic and normal membranes, ovalocytes required an 8–10-fold increase in applied shear stress, indicating that their membrane was capable of deforming under sufficient stress. To test the possibility that this increased membrane rigidity might confer resistance to parasitic invasion, we performed an in vitro invasion assay using Plasmodium falciparum merozoites and Malayan ovalocytes of varying deformability from seven different donors. The level of infection of the ovalocytes ranged from 1% to 35% of that in control cells, and the extent of inhibition appeared to be closely related to the reduction in membrane deformability. Moreover, we were able to induce similar resistance to parasitic invasion in nonovalocytic normal red cells by increasing their membrane rigidity with graded exposure to a protein crosslinking agent. Our findings suggest that resistance to parasite invasion of Malayan ovalocytes is the result of a genetic mutation that causes increased membrane rigidity.

Blood Groups in Infection and Host Susceptibility

“…In areas of the western Pacific where malaria is endemic, the incidence of SAO can reach 35% of the population. It was initially believed that increased red cell rigidity may interfere with parasite invasion, based on early reports of decreased parasitemia in SAO individuals (530)(531)(532). Later studies, however, found no difference between SAO and the incidence of asymptomatic malaria (529,533), type of malarial species (533,534), or level of parasitemia (533,535).…”

The malaria-infected red blood cell: Structural and functional changes

“…The red blood cell has become one of the pre-eminent systems for the analysis of structure-function relationships of biological membrane systems. It is probably the best understood eukaryotic cell in terms of the physical nature of the membrane skeleton and its relationship to the mechanical properties of the cell (Evans and Hochmuth, 1977;Mohandas et al, 1984Mohandas et al, , 1992Chasis and Mohandas, 1986;Mohandas, 1992;Mohandas and Chasis, 1993;Mohandas and Evans, 1994). The ordered arrangement of spectrin tetramers, their interconnection at the ternary complex with actin and protein 4.1, and the bonds to the overlying cell membrane via band 3 and glycophorin C ( Figure 1A) provide the basis for the cell's ability to deform during repeated passage through the microcirculation during its 120 days' lifetime (Bennett, V., 1983;Gardner, K. and Bennett, 1989;Mohandas and Evans, 1994).…”

“…Of those that act through changes in the red blood cell, the best known are probably the haemoglobinopathies such as sickle cell disease and the thalassaemias. The pathobiology of red blood cells in these conditions has been reviewed in detail (Evans and Hochmuth, 1977;Mohandas et aL, 1984Mohandas et aL, , 1992Chasis and Mohandas, 1986;Mohandas, 1992;Mohandas and Chasis, 1993;Mohandas and Evans, 1994) and description of the pathophysiology of these conditions is outside the scope of this current review. Many of these conditions induce rheological changes in the red blood cell that parallel those caused by malaria infection, and it is instructive to compare them.…”

Membrane compartmentalization in Southeast Asian ovalocytosis red blood cells

“…The SAO mutation has been reported to protect against malaria morbidity (Genton et al , 1995), malaria invasion (Kidson et al , 1981; Hadley et al , 1983; Cortes et al , 2004), and malaria parasitaemia (Cattani et al , 1987), and may be correlated with a decreased incidence of cerebral malaria (Allen et al , 1999; Gallagher, 2004; Lin et al , 2010). As we and others have suggested, the protective mechanism may involve increased rigidity of the SAO RBC membrane (Mohandas et al , 1984, 1992; Schofield et al , 1992b; Liu et al , 1995), which could potentially provide protection both by decreasing infected RBC adherence to vascular endothelium and by hindering parasite invasion of RBCs (Jakobsen et al , 1994; McCormick et al , 1997; Armah et al , 2005; Cortes et al , 2005; Medana & Turner, 2006; Conroy et al , 2010). An alternative view has been presented by Dluzewski et al (1992), who propose that P. falciparum invasion is high in fresh SAO RBCs and low in stored RBCs, which have low ATP levels.…”

“…SAO RBCs contain approximately 50% normal band 3 molecules and 50% mutant band 3 molecules (Liu et al , 1990; Bruce et al , 2000). SAO RBCs are abnormally rigid (Mohandas et al , 1984), and this rigidity may underlie the association between the SAO phenotype and clinical resistance to cerebral malaria (Genton et al , 1995).…”