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. Iron deficiency and supplementation can influence the risk and outcome of malaria infection. Epidemiology studies have indicated that iron deficiency anemia (IDA) is associated with a reduced risk of malaria in children and pregnant women (1-5), whereas clinical trials have demonstrated that iron supplementation in the absence of adequate health care increases the risk of malaria (6, 7). While the mechanisms underlying these outcomes are not well defined, it is clear that two major factors contribute: iron bioavailability and erythrocyte physiology.Iron bioavailability and homeostasis in the host during malaria infection are complex and incompletely understood (8). During infection, expression of the iron-regulatory hormone hepcidin increases significantly, leading to reduced dietary iron absorption and increased iron storage (9-12). The restriction of iron bioavailability may be a host defense mechanism designed to inhibit parasite access to iron, although the source of iron utilized by the parasite is still unclear (13,14). In liver-stage infection, reduced iron bioavailability brought on by previously ...

Increased Plasmodium chabaudi malaria mortality in mice with nutritional iron deficiency can be reduced by short-term adjunctive iron supplementation

“…Both altered iron bioavailability and erythrocyte physiology have been implicated as mechanisms underlying the putative protective effect of iron deficiency [ 19 , 40 ]. Clark et al speculated that iron deficiency might induce a reduction in the erythropoietic rate and the synthesis of microcytic, iron-deficient erythrocytes unsuitable as host cells for the parasites [ 41 ].…”

“…To some extent, these difficulties can be overcome in studies of experimental animal models of malaria, as these allow full control over the cause, degree, and alleviation of iron deficiency, as well as control over the timing and clinical consequences of malaria infection in iron-deficient and iron-replete animals. Nevertheless, such studies have also shown conflicting results [ 15 – 19 ].…”

The hypolipidemic effects of Tamarindus indica fruit pulp extract in normal and diet‐induced hypercholesterolemic hamsters are associated with altered levels of serum proteins

“…TF, an acute‐phase protein synthesized in the liver, is mainly involved in binding and transportation of iron in the blood circulation. Decreased levels of TF have been associated with diabetes mellitus , inflammation and infection . Furthermore, TF has been postulated to control oxidative stress by increasing uptake of iron .…”

Digoxin-induced anemia among patients with atrial fibrillation and heart failure: clinical data analysis and drug-gene interaction network

“…For instance, TFRC gene (i.e., transferrin receptor) encodes a cell surface receptor necessary for cellular iron uptake, which is essential for development of red blood cells [ 18 ]. And iron deficiency anemia is observed in a mouse model of missense mutation in TFRC [ 19 ]. As another example, PICALM gene (i.e., phosphatidylinositol binding clathrin assembly) interacts with TFRC as a critical regulator of transferrin receptor endocytosis [ 20 ].…”