Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum

Abstract

Iron deficiency and malaria have similar global distributions, and frequently co-exist in pregnant women and young children. Where both conditions are prevalent, iron supplementation is complicated by observations that iron deficiency anaemia protects against falciparum malaria, and that iron supplements increase susceptibility to clinically significant malaria, but the mechanisms remain obscure. Here, using an in vitro parasite culture system with erythrocytes from iron-deficient and replete human donors, we demonstrate that Plasmodium falciparum infects iron-deficient erythrocytes less efficiently. In addition, owing to merozoite preference for young erythrocytes, iron supplementation of iron-deficient individuals reverses the protective effects of iron deficiency. Our results provide experimental validation of field observations reporting protective effects of iron deficiency and harmful effects of iron administration on human malaria susceptibility. Because recovery from anaemia requires transient reticulocytosis, our findings imply that in malarious regions iron supplementation should be accompanied by effective measures to prevent falciparum malaria.

Cord Blood Hepcidin: Cross-Sectional Correlates and Associations with Anemia, Malaria, and Mortality in a Tanzanian Birth Cohort Study

“…Clinicians monitored children's health statuses during sick visits and at routine visits occurring on a biweekly basis during the first 12 months of life and a monthly basis for any follow-up beyond the first year. Children's hemoglobin was measured at sick visits and during routine visits at approximately 3,6,12,18,24,30,36,42, and 48 months of age. Parasitemia by P. falciparum was determined after counting 200 leukocytes on Giemsa-stained thick blood smear of a sample collected by heel or finger prick during child visits.…”

“…11 During the blood stage, iron deficiency may confer a protective effect by impairing the ability of Plasmodium falciparum to invade and propagate between erythrocytes. 12 In addition, recent experiments have also found that hepcidin-induced iron redistribution away from hepatocytes arrests the growth of intrahepatocytic parasites and thereby prevents the occurrence of malaria superinfections. 13 Epidemiological studies lend support to these findings: pregnant women and children who are iron deficient are observed to have lower risks of malarial disease, [14][15][16][17][18] and pediatric iron supplementation has been shown to heighten the risk of both clinical and severe malaria.…”

Hepcidin in the diagnosis of iron disorders

“…6,58 This fascinating hypothesis, requiring the development of a validated point-of-care hepcidin assay, is actively under evaluation. However, because iron-induced reticulocytosis could increase susceptibility to malaria, 76 and low hepcidin values do not necessarily exclude a concurrent infection, 46 safe iron supplementation in malaria-endemic areas should entail not only the ability to absorb and incorporate iron but also effective measures to prevent exacerbations of infections.…”

Factor XIIIa-dependent retention of red blood cells in clots is mediated by fibrin α-chain crosslinking

“…RBCs were age separated using density gradient centrifugation 25 (detailed in supplemental Methods). ), were expressed and purified as described in the supplemental Methods.…”