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

Abstract

High frequency of erythrocyte (red blood cell [RBC]) genetic disorders such as sickle cell trait, thalassemia trait, homozygous hemoglobin C (Hb-C), and glucose-6-phosphate dehydrogenase (G6PD) deficiency in regions with high incidence of Plasmodium falciparum malaria and casecontrol studies support the protective role of those conditions. Protection has been attributed to defective parasite growth or to enhanced removal of the parasitized RBCs. We suggested enhanced phagocytosis of rings, the early intraerythrocytic form of the parasite, as an alternative explanation for protection in G6PD deficiency. We show here that P falciparum developed similarly in normal RBCs and in sickle trait, beta-and alpha-thalassemia trait, and HbH RBCs. We also show that membrane-bound hemichromes, autologous immunoglobulin G (IgG) and complement IntroductionHigh frequency of hemoglobinopathies such as sickle cell trait, thalassemia trait, homozygous hemoglobin C (Hb-C) and Hb-E; glucose-6-phosphate dehydrogenase (G6PD) deficiency; and Southeast Asian ovalocytosis (SAO) in regions with past or present high incidence of Plasmodium falciparum malaria and case-control studies support the protective role of those conditions (see Roberts et al 1 ; Weatherall 2 ; Greene 3 ; and Serjeantson et al 4 for reviews). Protection has been attributed in some studies to defective invasion or growth of the parasite in the mutant erythrocytes (red blood cells [RBCs]), 5-7 while other studies found normal parasite invasion and growth. 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. 14-16 Recently, we found that several strains of P falciparum developed similarly in normal and G6PD-deficient RBCs. 9 However, ring-parasitized G6PD-deficient RBCs bound more opsonins such as autologous immunoglobulin G (IgG) and complement C3c fragments, and were phagocytosed more intensely than their normal counterparts. 9 We suggested enhanced ring phagocytosis as an alternative explanation for malaria protection in G6PD-deficient individuals, and discussed why removal of early parasite forms could be advantageous to the host. 9 We show here that P falciparum invaded and matured similarly in normal and mutant RBCs (heterozygous sickle cell anemia [HbAS]; heterozygous beta-thalassemia [beta-thal trait]; homozygotes for alpha-plus thalassemia [alpha-thal trait]; compound heterozygotes for alpha-zero and alpha-plus thalassemia [HbH disease]) up to the third cycle of invasion. We also show that membrane-bound hemichromes, ag...

An investigation of the protective effect of alpha+‐thalassaemia against severe Plasmodium falciparum amongst children in Kumasi, Ghana

“…According to Ayi et al, (2004) Plasmodium falciparum malaria to the homozygotes sickle cell individual is offset by the survival advantage of heterozygotes in malaria endemic areas.…”

The genetics of blood disorders: the hereditary hemoglobinopathies

“…A redução do ácido siálico, como ocorre em hemácias normais senescentes, leva a uma maior exposição de resíduos β-galactosil, reconhecidos por anticorpos IgG antigalactosil que promovem o seqüestro das células pelo sistema reticuloendotelial 95,96 .…”

Association of a new mannose-binding lectin variant with severe malaria in Gabonese children

“…In the heterozygotic state, they enhance the removal of erythrocytes parasitized by the younger stages of the parasite, whereas in the homozygotic state they can be lethal. 3 These polymorphisms are probably maintained in malaria-affected populations by balancing selection. Other genetic variants that modulate the immune response were also found associated with protection against severe outcomes of the disease.…”