title: Erythrocytic Iron Deficiency Enhances Susceptibility to Plasmodium chabaudi Infection in Mice Carrying a Missense Mutation in Transferrin Receptor 1.
abstract: 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.
authors: Australian National University, John Curtin School of Medical Research, Canberra, ACT, Australia, and Macquarie University, Australian School of Advanced Medicine, Sydney, NSW, Australia.
authors: Patrick M
authors: PM
authors: Lelliott
authors: Australian National University, John Curtin School of Medical Research, Canberra, ACT, Australia, and Macquarie University, Australian School of Advanced Medicine, Sydney, NSW, Australia.
authors: Brendan J
authors: BJ
authors: McMorran
authors: Australian National University, John Curtin School of Medical Research, Canberra, ACT, Australia, and Macquarie University, Australian School of Advanced Medicine, Sydney, NSW, Australia.
authors: Simon J
authors: SJ
authors: Foote
authors: Australian National University, John Curtin School of Medical Research, Canberra, ACT, Australia, and Macquarie University, Australian School of Advanced Medicine, Sydney, NSW, Australia Gaetan.Burgio@anu.edu.au.
authors: Gaetan
authors: http://orcid.org/0000-0002-7434-926X
authors: G
authors: Burgio
mesh_terms: D000818:Animals; D004198:Disease Susceptibility; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006801:Humans; D000090463:Iron Deficiencies; D008288:Malaria / Q000097:blood / Q000469:parasitology*; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D016788:Plasmodium chabaudi / Q000502:physiology*; D011990:Receptors, Transferrin / Q000235:genetics* / Q000378:metabolism
chemical_list: D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse