The Haldane malaria hypothesis: facts, artifacts, and a prophecy

Abstract

Heterozygous thalassemia and sickle cell disease produce mild hematological symptoms but provide protection against malaria mortality and severe malaria symptoms. Two explanations for resistance are considered in the literature - impaired growth of the parasite or enhanced removal by the host immune cells. A critical overview of studies that connect malaria resistance with impaired intra-erythrocytic growth is presented. All studies are fraught with two kinds of bias. The first one resides in the impossibility of reproducing the in vivo situation in the simplified model in vitro. The second stems from the generalized use of RPMI 1640 culture medium. RPMI 1640 has critically low levels of several amino acids; is devoid of hypoxanthine (essential for parasite growth) and adenine; and is low in reduced glutathione. Analysis of representative studies indicates that impaired parasite growth in heterozygous red blood cells (RBCs) may derive from nutrient limitations and, therefore, possibly be of artefactual origin. This conclusion seems plausible because studies were performed with RPMI 1640 medium at relatively high hematocrit and for prolonged periods of time. Mutations considered are particularly sensitive to nutrient deprivation because they have higher metabolic demands due to permanent oxidant stress related to unpaired globin chains, sickle hemoglobin and high levels of membrane-free iron. In addition, non-parasitized AS- and thalassemic-RBCs are dehydrated and microcytic. Thus, the number of metabolically active elements per unit of blood volume is remarkably larger in mutant RBCs compared to normocytes. The latter point may represent a confirmation of Haldane's prophetic statement: 'The corpuscles of the anaemic heterozygotes are smaller than normal, and more resistant to hypotonic solutions. It is at least conceivable that they are also more resistant to attacks by the sporozoa which cause malaria.'

Mechanisms of genetically-based resistance to malaria

“…Firstly, it has been shown that intra-erythrocytic parasite growth is greatly inhibited by HbS polymerization when oxygen levels drop below 5%. Secondly, higher parasite-infected sickle erythrocyte phagocytosis by host immune cells has been observed when compared to infected normal erythrocytes (Smith et al, 2002;Akide-Ndunge et al, 2003;Roberts and Williams, 2003;Ayi et al, 2004;Cabrera et al, 2005).…”

“…According to Haldane's malaria hypothesis (Haldane, 1949;Yuthavong and Wilairat, 1993;Smith et al, 2002;Duffy and Fried, 2006;Pasvol, 2006), this could result in a "balanced polymorphism" where the homozygote's hematological disadvantage is balanced by the resistance to malaria displayed by the heterozygote (Yuthavong and Wilairat, 1993;Agarwal et al, 2000;Smith et al, 2002;Akide-Ndunge et al, 2003).…”

Ion Transport Pathology in the Mechanism of Sickle Cell Dehydration

“…Two general protective mechanisms had been considered in the literature: restricted parasite growth and enhanced immune retrieval of the parasitized RBCs. Much of the early work is conflictive and confusing, mainly because of the limitations of in vitro studies to reproduce the conditions in vivo (1). Recent work (9,59,135) strongly suggests that resistance in AS RBCs is caused by enhanced phagocytosis of RBCs infected with ring stage parasites in response to alterations of the membrane surface associated with increased hemichrome formation, aggregated band 3, elevated autologous IgG, and complement C3c fragments.…”

The hydration state of human red blood cells and their susceptibility to invasion by Plasmodium falciparum

“…43,44 These abnormalities may affect the structure of hemoglobin, 45,46 the RBC membrane, 47,48 or RBC metabolism, [49][50][51] generating a large diversity of pathologies affecting millions of people worldwide. The most widely distributed of these pathologies are sickle cell anemia, thalassemias, 52-54 ovalocytosis, 48,55 hereditary spherocytosis, 56 and glucose-6-phosphate dehydrogenase (G6PD) deficiency.…”