The treatment of
iron deficiency in areas of high
malaria transmission is complicated by evidence which suggests that
iron deficiency anemia protects against
malaria, while
iron supplementation increases
malaria risk.
Iron deficiency anemia results in an array of pathologies, including reduced systemic
iron bioavailability and abnormal erythrocyte physiology; however, the mechanisms by which these pathologies influence
malaria infection are not well defined. In the present study, the response to
malaria infection was examined in a mutant mouse line, Tfrc(MRI24910), identified during an
N-ethyl-N-nitrosourea (ENU) screen. This line carries a missense mutation in the gene for
transferrin receptor 1 (TFR1). Heterozygous mice exhibited reduced erythrocyte volume and density, a phenotype consistent with
dietary iron deficiency
anemia. However, unlike the case in dietary deficiency, the erythrocyte half-life, mean corpuscular hemoglobin concentration, and intraerythrocytic
ferritin content were unchanged. Systemic
iron bioavailability was also unchanged, indicating that this mutation results in erythrocytic
iron deficiency without significantly altering overall
iron homeostasis. When infected with the rodent
malaria parasite Plasmodium chabaudi adami, mice displayed increased
parasitemia and succumbed to
infection more quickly than their wild-type littermates. Transfusion of fluorescently labeled erythrocytes into
malaria parasite-infected mice demonstrated an erythrocyte-autonomous enhanced survival of parasites within mutant erythrocytes. Together, these results indicate that TFR1 deficiency alters erythrocyte physiology in a way that is similar to
dietary iron deficiency
anemia, albeit to a lesser degree, and that this promotes intraerythrocytic parasite survival and an increased susceptibility to
malaria in mice. These findings may have implications for the management of
iron deficiency in the context of
malaria.