Anemia Offers Stronger Protection Than Sickle Cell Trait Against the Erythrocytic Stage of Falciparum Malaria and This Protection Is Reversed by Iron Supplementation

Abstract

BackgroundIron deficiency causes long-term adverse consequences for children and is the most common nutritional deficiency worldwide. Observational studies suggest that iron deficiency anemia protects against Plasmodium falciparum malaria and several intervention trials have indicated that iron supplementation increases malaria risk through unknown mechanism(s). This poses a major challenge for health policy. We investigated how anemia inhibits blood stage malaria infection and how iron supplementation abrogates this protection.MethodsThis observational cohort study occurred in a malaria-endemic region where sickle-cell trait is also common. We studied fresh RBCs from anemic children (135 children; age 6–24 months; hemoglobin < 11 g/dl) participating in an iron supplementation trial (ISRCTN registry, number ISRCTN07210906) in which they received iron (12 mg/day) as part of a micronutrient powder for 84 days. Children donated RBCs at baseline, Day 49, and Day 84 for use in flow cytometry-based in vitro growth and invasion assays with P. falciparum laboratory and field strains. In vitro parasite growth in subject RBCs was the primary endpoint.FindingsAnemia substantially reduced the invasion and growth of both laboratory and field strains of P. falciparum in vitro (~ 10% growth reduction per standard deviation shift in hemoglobin). The population level impact against erythrocytic stage malaria was 15.9% from anemia compared to 3.5% for sickle-cell trait. Parasite growth was 2.4 fold higher after 49 days of iron supplementation relative to baseline (p < 0.001), paralleling increases in erythropoiesis.InterpretationThese results confirm and quantify a plausible mechanism by which anemia protects African children against falciparum malaria, an effect that is substantially greater than the protection offered by sickle-cell trait. Iron supplementation completely reversed the observed protection and hence should be accompanied by malaria prophylaxis. Lower hemoglobin levels typically seen in populations of African descent may reflect past genetic selection by malaria.FundingNational Institute of Child Health and Development, Bill and Melinda Gates Foundation, UK Medical Research Council (MRC) and Department for International Development (DFID) under the MRC/DFID Concordat.

Safety and benefits of antenatal oral iron supplementation in low‐income countries: a review

“…The same group has recently shown this to be true in Gambian children and that it applies both to laboratory and local clinical strains of P. falciparum (Goheen et al , 2016). They have further shown that young erythrocytes are more susceptible to invasion and propagation by P. falciparum merozoites than mature erythrocytes (Clark et al , 2014a,b; Goheen et al , 2016).…”

“…The same group has recently shown this to be true in Gambian children and that it applies both to laboratory and local clinical strains of P. falciparum (Goheen et al , 2016). They have further shown that young erythrocytes are more susceptible to invasion and propagation by P. falciparum merozoites than mature erythrocytes (Clark et al , 2014a,b; Goheen et al , 2016). Seven weeks of iron supplementation completely abrogated the protection offered by iron deficiency anaemia in both Gambian children (Goheen et al , 2016) and pregnant Gambian women (Drs Goheen, Bah & Cerami, MRC Unit The Gambia, Banjul, The Gambia, personal communication).…”

“…They have further shown that young erythrocytes are more susceptible to invasion and propagation by P. falciparum merozoites than mature erythrocytes (Clark et al , 2014a,b; Goheen et al , 2016). Seven weeks of iron supplementation completely abrogated the protection offered by iron deficiency anaemia in both Gambian children (Goheen et al , 2016) and pregnant Gambian women (Drs Goheen, Bah & Cerami, MRC Unit The Gambia, Banjul, The Gambia, personal communication). These results indicate that the increased erythropoiesis and thus, the greater availability of young erythrocytes in response to iron supplementation leads to a transient increase in P. falciparum malaria risk in iron‐deficient individuals but not in their iron‐replete peers.…”

Clinical Implications of New Insights into Hepcidin-Mediated Regulation of Iron Absorption and Metabolism

“…This has been driven by the hazardous nature of iron; both in causing oxidative damage and in promoting the growth of microorganisms. There is clear evidence that a moderate degree of iron deficiency anemia is highly protective against malaria [28] and likely protective against a range of bacterial and fungal pathogens [23] and possibly viruses [41] . This has resulted in the evolution of exquisite systems for chaperoning iron and regulating its intake and organ distribution.…”

“…Hepcidin-induced hypoferremia in circulating plasma protects against the acute threat of bacterial and yeast sepsis. Prolonged upregulation of hepcidin leads to the anemia of inflammation or of chronic infection [27] , which in turn protects against the blood stage of malarial infection [28] . Similarly, hypoferremia in hepatocytes protects against the hepatic stages of malaria infection [29] .…”