Interaction between oxidized hemoglobin and the cell membrane: A common basis for several falciparum malaria‐linked genetic traits

Abstract

KEY WORDSlinked genetic traits, Membrane bound hemoglobin Oxidative stress, falciparum malaria, Malaria- ABSTRACTThis paper focuses on the interaction between oxidized hemoglobin and the erythrocyte membrane, and its relevance to some falciparum malaria-linked genetic traits. We first present the experimental evidence which suggests that the interaction between hemoglobin derivatives and membrane proteins is an important cellular mechanism for the erythrocytes carrying HbS, HbE, HbF, a-and P-thalassemia, and GGPD deficiency. Thereafter, we show how the Hblmembrane interaction might act as primum movens for diverse cellular mechanisms which 1) reduce invasion of erythrocytes by the falciparum parasite; 2) impair parasite survival and development within the cell; 3) accelerate infected erythrocyte clearance by phagocytosis. We claim that oxidative stress is the driving force of this process, since highly reactive species (like 0,-and H202) mediate the gradual oxidation of Hb to irreversible hemichrome-containing Heinz bodies. We therefore suggest that positing the interaction between oxidized hemoglobin and cell membrane as a common basis for several falciparum malaria-linked genetic traits is not only consistent with experimental evidence gathered so far, but provides a new, clearer perspective: the molecular event on which these known protective traits rest. In the last part of the paper we will discuss two case studies which provide further support for the role played by hemoglobin derivatives and membrane proteins: 1) the influence of a cyanogen-rich diet on the distribution of HbPV gene frequencies in Liberia (Jackson [1990] Am.

Malaria: Genetic and Evolutionary Aspects

“…This model of resistance, which involves an enhanced phagocytosis of ring-parasitized mutant RBC, was earlier proposed by Cappodoro et al (1998) for G6PD deficiency and was later extended to Hb AS, beta-thalassemia trait, and Hb H by Ayi et al (Blood, in press). It has been noted that several protective mutations have phenotypic similarities, although differing in the molecular nature of the underlying defect (Destro-Bisol et al, 1996). As expected, higher levels of bound antibodies and more intense phagocytosis have been observed in parasitized thalassemic and other mutant RBC.…”

Enhanced phagocytosis of ring-parasitized mutant erythrocytes: a common mechanism that may explain protection against falciparum malaria in sickle trait and beta-thalassemia trait

“…Possible reasons may reside in the limited amount of mobile band 3 in the RBC membrane 37 and in the physical limit of 10 RBCs ingested per monocyte. 27 The evident similarities among many protective mutations have been noted in several studies (see Destro-Bisol et al 11 and Anastasi 38 for review). Not surprisingly, higher levels of bound antibodies and more intense phagocytosis have been described in parasitized thalassemic and other mutant RBCs.…”

“…15,16 Thus, enhanced removal of parasitized mutant RBCs by the host's immune system has been suggested as the mechanism underlying resistance. 11,15,16 The model presented here is also based on preferential immunologic removal of mutant RBCs, but it has the distinctive feature that only phagocytosis of ring-parasitized mutant RBCs is selectively enhanced, while phagocytosis of trophozoites is very high but quite similar in normal and mutant cells. This model of resistance based on enhanced phagocytosis of ring-parasitized For personal use only.…”

“…8,9 Since the original proposal by Haldane, 10 microcitemia and increased osmotic resistance, enhanced oxidant radical production due to unpaired globin chains, increased sickling, ionic unbalances or membrane rigidity, or molecular defects in band 3 have been suggested as underlying mechanisms explaining impaired growth of the parasite in the mutant RBCs. [1][2][3][4][5][11][12][13] Other studies have found increased deposition of nonspecific autologous antibodies on malaria-parasitized mutant RBCs and suggested phagocytic elimination as the possible mechanism of protection in nonimmune subjects. [14][15][16] Recently, we found that several strains of P falciparum developed similarly in normal and G6PD-deficient RBCs.…”

The triumph of good over evil: protection by the sickle gene against malaria

“…32 There is experimental evidence that oxidant damage is a common mechanism shared by AS RBCs, ␤-and ␣-thalassemias as well as G6PD deficiency in mediating resistance to malaria. 33,34 It is likely that when these RBCs are parasitized they are subjected to additional oxidative stress because of enhanced generation of ROS by both the parasite and the mutant RBC. However, it is uncertain whether the enhanced oxidant stress of these mutant RBCs impacts more on impairing parasite growth or enhancing uptake by phagocytes.…”