Abstract
Iron deficiency is the most widespread nutritional deficiencies in the developing world and iron is commonly administered compounds through mass distribution campaigns. However, recent evidence suggests that iron deficiency may protect against malaria and that iron supplementation may increase susceptibility to malaria, complicating recommendations for universal supplementation in malaria‐endemic regions. It has been previously hypothesized that iron deficiency inhibited malaria growth through iron deprivation, as is the case with other pathogens. However, our work has generated a novel hypothesis for the effect of iron deficiency and iron supplementation on parasite growth ‐ namely that changes in RBC physiology and RBC age population structure drive resistance of RBCs from IDA donors and increased susceptibility of RBCs from iron supplemented IDA donors to malaria Using an in vitro system with RBCs from donors with well‐defined physiological iron states, we have investigated the cellular mechanisms associated with malaria protection by iron‐deficiency anemia (IDA). We described multiple IDA impacts on parasites, including attenuated invasion of IDA red blood cells (RBCs) and reduced production of parasite progeny. We demonstrate that as iron deficient individuals increase their rate of erythropoiesis in response to iron supplementation, their RBCs becomes more susceptible to infection. Additionally, we show that the replacement of iron deficient RBCs with young normocytic iron‐replete RBCs increases susceptibility to P. falciparum infection. Our results provide a cautionary message to well‐intentioned public health workers who follow the current World Health Organization recommendation to routinely provide iron supplements to iron‐deficient children.Grant Funding Source: National Institute of Child Health and Human Development under award number U01HD061235
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