Malaria and iron deficiency are interconnected public health concerns, which disproportionally affect children and pregnant women. Malaria causes an estimated 250 million infections and 1 million deaths per year. Plasmodium falciparum is the most virulent species of the malaria parasite that infects humans. Anemia, predominantly iron deficiency anemia, is the most common nutritional deficiency worldwide, and affects up to 50% of populations in the developing world. The World Health Organization recommends universal iron supplementation in regions where malnutrition is common. This recommendation has been complicated by clinical evidence that iron deficiency protects against malaria infection, and that iron supplementation increases susceptibility to malaria infection. The mechanisms underlying the interaction between malaria, host iron, and iron supplementation remain unclear. Here, I've employed the in vitro system for cultivating erythrocytic stage P. falciparum to assess first, the impact of extracellular iron on parasite growth as well as the bioavailable iron content of parasitized erythrocytes. I have found that extracellular iron is incorporated into parasitized erythrocytes but does not have affect parasite growth. Second, I assessed the capacity of erythrocytes from iron deficient and iron supplemented donors to support erythrocytic stage P. falciparum growth. In these studies I observed that P. falciparum propagation is reduced in iron deficient erythrocytes and that reduced parasite propagation is a result of decreased parasite invasion into iron deficient erythrocytes as well as decreased production of infectious daughter merozoites within iron deficient erythrocytes. I additionally observe that P. falciparum propagation is recovered in erythrocytes donated by iron supplemented iron deficient donors. Furthermore, I attribute the recovery of P. falciparum erythrocyte propagation to the replacement of iron deficient erythrocytes with young iron-replete erythrocytes that are produced in response to iron supplementation. These results are consistent with clinical observations that iron deficiency is protective against malaria infection and iron supplementation increases the risk of malaria infection. Moreover, my results suggest that iron mediated alterations to erythrocyte physiology and intra-host erythrocyte population dynamics as well as potentially altered serum iron levels contribute to the underlying mechanisms governing the relationship between the malaria parasite, iron deficiency, and iron supplementation.Doctor of Philosoph
