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

Filip C Castberg,Lasse Maretty,Erik Clasen-Linde,Lars Hviid,Trine Staalsoe,Jørgen A L Kurtzhals,Casper Hempel

doi:10.1186/s12936-018-2186-8

Abstract

BackgroundIron deficiency is the most widespread nutrient deficiency and an important cause of developmental impairment in children. However, some studies have indicated that iron deficiency can also protect against malaria, which is a leading cause of childhood morbidity and mortality in large parts of the world. This has rendered interventions against iron deficiency in malaria-endemic areas controversial.MethodsThe effect of nutritional iron deficiency on the clinical outcome of Plasmodium chabaudi AS infection in A/J mice and the impact of intravenous iron supplementation with ferric carboxymaltose were studied before and after parasite infection. Plasma levels of the iron status markers hepcidin and fibroblast growth factor 23 were measured in animals surviving and succumbing to malaria, and accompanying tissue pathology in the liver and the spleen was assessed.ResultsNutritional iron deficiency was associated with increased mortality from P. chabaudi malaria. This increased mortality could be partially offset by carefully timed, short-duration adjunctive iron supplementation. Moribund animals were characterized by low levels of hepcidin and high levels of fibroblast growth factor 23. All infected mice had extramedullary splenic haematopoiesis, and iron-supplemented mice had visually detectable intracellular iron stores.ConclusionsBlood transfusions are the only currently available means to correct severe anaemia in children with malaria. The potential of carefully timed, short-duration adjunctive iron supplementation as a safe alternative should be considered.

Highlights

Iron deficiency is the most widespread nutrient deficiency and an important cause of developmental impairment in children
Iron deficiency has been proposed to protect against malaria [7,8,9,10], and there is some evidence that iron
Determination of appropriate inoculum size To establish an appropriate inoculum size that would result in mortality in some but not all infected control animals, groups of mice i.p. were inoculated with increasing numbers of infected erythrocytes (IEs) (1 × 104 − 5 × 106) (Fig. 1)

Summary

Introduction

Iron deficiency is the most widespread nutrient deficiency and an important cause of developmental impairment in children. Some studies have indicated that iron deficiency can protect against malaria, which is a leading cause of childhood morbidity and mortality in large parts of the world. This has rendered interven‐ tions against iron deficiency in malaria-endemic areas controversial. Castberg et al Malar J (2018) 17:34 measurements, adding further complexity to epidemiological studies in malaria-endemic areas [14] 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 irondeficient and iron-replete animals. This supplement offers a cost-effective and fast correction of iron deficiency that overcomes the defective absorption of oral iron among parasitaemic recipients, and is without the adverse effects of earlier intravenous preparations

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