Combinatorial effects of malaria season, iron deficiency, and inflammation determine plasma hepcidin concentration in African children

Atkinson, Sarah H.; Armitage, Andrew E.; Khandwala, Shivani; Mwangi, Tabitha; Uyoga, Sophie; Bejon, Philip; Williams, Thomas N.; Prentice, Andrew M.; Drakesmith, Hal

doi:10.1182/blood-2013-10-533000

Cited by 60 publications

(65 citation statements)

References 41 publications

(62 reference statements)

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“…There is considerable variability in the hepcidin concentrations obtained with the different methods, even when using comparable samples, making further standardization essential before the tests can be implemented clinically (43). Nevertheless, serum or urine hepcidin levels have been shown to be significantly elevated in a number of human inflammatory conditions, including IBD, rheumatoid arthritis, malaria, human immunodeficiency virus infection and neonatal sepsis (19-22,44-47). …”

Section: Dysregulation Of Iron Metabolism By Inflammationmentioning

confidence: 99%

Pathophysiology of Iron Homeostasis during Inflammatory States

Cherayil

2015

The Journal of Pediatrics

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Section: Dysregulation Of Iron Metabolism By Inflammationmentioning

confidence: 99%

Pathophysiology of Iron Homeostasis during Inflammatory States

Cherayil

2015

The Journal of Pediatrics

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“…The same assay was also performed using P. yoelii-infected host animals, except that an extended series of time points were examined (12,36, and 60 h) (Fig. 6).…”

Section: Fig 3 Susceptibility Of Tfrcmentioning

confidence: 99%

“…During infection, expression of the iron-regulatory hormone hepcidin increases significantly, leading to reduced dietary iron absorption and increased iron storage (9)(10)(11)(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).…”

mentioning

confidence: 99%

Erythrocytic Iron Deficiency Enhances Susceptibility to Plasmodium chabaudi Infection in Mice Carrying a Missense Mutation in Transferrin Receptor 1

et al. 2015

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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 ...

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“…In Beninese women with asymptomatic P falciparum infection, antimalarial treatment increased mean dietary iron absorption from 10% to 18% 32. Complementing this, the prevalence of iron deficiency and iron deficiency anaemia was significantly higher at the end of malaria season compared with the start in rural west and east African preschool children, suggesting suppression of iron absorption by infection 33. Moreover, interruption of malaria transmission for 12 months in rural Kenya reduced the prevalence of iron deficiency in young children from 35% to 26%, and anaemia from 54% to 32% 34…”

Section: New Insights Into Iron-infection Interactionsmentioning

confidence: 76%