Resistance to Falciparum malaria in α‐thalassemia, oxidative stress, and hemoglobin oxidation

Abstract

A recent survey conducted on Vanuatu Island suggests that resistance to Plasmodium falciparum in alpha-thalassemic individuals may have an immunological basis. This study is important since it seems to undermine the current idea that red-cell genetic defects give protection against falciparum malaria by reducing intraerythrocytic growth and development of the parasite. However, the mechanisms underlying these clinical and genetic observations are not yet fully understood. Based on a review of the relevant literature, we first show that the model based on the interaction between hemoglobin (Hb) and membrane components may provide a molecular basis for the involvement of the immune response in genetic adaptation to malaria. Second, we discuss the main evolutionary implications of the model. Finally, we suggest two approaches by which anthropological studies could provide a useful way of testing the model: 1) analysis of the interactions of malaria-resistance genes with genetic polymorphisms which affect the erythrocyte redox status and 2) study of the antimalarial effects of natural products (introduced as a part of a diet or for traditional antimalarial therapy) capable of interfering with the Hb/membrane interaction.

Preconditioning with Hemin Decreases Plasmodium chabaudi adami Parasitemia and Inhibits Erythropoiesis in BALB/c Mice

“…Considering that the inhibitory effects on parasitemia measured in hemin-preconditioned mice were apparent at early infection, it seems plausible that hemin renders RBCs less prompt to infection by merozoites or less apt in generating high numbers of merozoites during the first waves of parasite replication. By affecting the rigidity of RBC membranes heme may interfere with parasite penetration in the RBC [45], since it intercalates in the membrane bi-layer and oxidizes membrane phospholipids. The negative impact for hemin on P. c. adami DK parasitemia greatly contrasts with the absence of effect of hemin reported by Ferreira et al on P. berghei parasitemia [42].…”

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

“…Additionally, alpha+-thalassaemia RBCs age more quickly, due to oxidative stress when parasites breaks-down erythrocytes leading to membrane damage, increased phagocytosis and decreased parasite invasion (Yuthavong et al, 1988;Destro-Bisol et al, 1999a;Senok et al, 2006).…”

“…Furthermore, surface antigens on the RBC undergo conformational changes when the parasite enters the thalassaemic red cells and appear to bind increased amounts of immunoglobulin, which might favour early removal of parasitized red blood cells (Luzzi et al, 1991a;Pattanapanyasat et al, 1999;Destro-Bisol et al, 1999a, DestroBisol et al, 1999b.…”

“…The protective effect by alpha+-thalassaemia against Plasmodium falciparum has been suggested to result from modified antigen recognition on the surface of the parasitized erythrocyte and the binding of thalassaemic red cells to increased amounts of immunoglobin and complement (Luzzi et al, 1991a;Luzzi et al, 1991b;Pattanapanyasat et al, 1999;Destro-Bisol et al, 1999a, Destro-Bisol et al, 1999b, Cockburn et al, 2004.…”

Redox and antioxidant systems of the malaria parasite Plasmodium falciparum

“…Notably, not only is the parasite itself under oxidative stress but the host cell also shows oxidative alterations when infected with Plasmodium . This is demonstrated by changes in erythrocyte membrane fluidity, most probably because of alterations of erythrocyte membrane lipid composition and protein cross‐linking (Destro Bisol, 1999; Giribaldi et al ., 2001; Williams et al ., 2002; Omodeo‐Sale et al ., 2003). Haemichrome accumulation on the inner surface of the parasitized erythrocytes as well as the aggregation of erythrocyte band 3 and the increasing occurrence of auto‐anti‐band 3 antibodies suggest that the host erythrocytes are severely oxidatively damaged by the Plasmodium infection (Parker et al ., 2004).…”