A critical role for phagocytosis in resistance to malaria in iron‐deficient mice

Matsuzaki-Moriya, Chikako; Tu, Liping; Ishida, Hidekazu; Imai, Takashi; Suzue, Kazutomo; Hirai, Makoto; Tetsutani, Kohhei; Hamano, Shinjiro; Shimokawa, Chikako; Hisaeda, Hajime

doi:10.1002/eji.201040942

Cited by 23 publications

(25 citation statements)

References 31 publications

(34 reference statements)

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“…This finding is at odds with the case for IDA erythrocytes, in which the parasite is more susceptible to clearance and therefore has a reduced rate of survival (22,23). Enhanced clearance in individuals with IDA is thought to be caused by increased phosphatidylserine exposure, which mediates increased phagocytosis, although the reasons for this increased exposure are unknown (22). Our results indicate that physiological characteristics, including microcytosis, density, and osmotic fragility of erythrocytes, do not necessarily influence erythrocyte susceptibility to invasion or the ability of erythrocytes to support parasite growth.…”

Section: Discussionmentioning

confidence: 92%

“…The effects imparted by the Tfrc MRI24910 mutation on parasitized erythrocytes could potentially affect one or more of these processes. This finding is at odds with the case for IDA erythrocytes, in which the parasite is more susceptible to clearance and therefore has a reduced rate of survival (22,23). Enhanced clearance in individuals with IDA is thought to be caused by increased phosphatidylserine exposure, which mediates increased phagocytosis, although the reasons for this increased exposure are unknown (22).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, Plasmodium falciparum invasion and replication are inhibited in iron-deficient erythrocytes compared to normal erythrocytes in vitro, although the reason for this has not been determined (21). In rodent malaria, parasitized iron-deficient erythrocytes are more likely to display phosphatidylserine, which results in enhanced phagocytosis of these cells relative to that of equivalent parasitized control erythrocytes (22,23). The reasons for this increased exposure are also undetermined.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…It should be noted that our work exclusively focuses on the influence of iron deficiency and iron supplementation on the susceptibility of the human host's RBC to malaria infection, and does not address the potential effect of serum iron 13 or additional factors, which may function in vivo, including growth of the hepatic stage of the parasite 34 , rosetting and cytoadherence to the endothelium, accelerated clearance of parasitized RBCs 35,36 , effects of innate immune factors such as hepcidin 11 and lipocalin 2 (ref. 37), or adaptive immune function.…”

Section: Discussionmentioning

confidence: 99%

Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum

et al. 2014

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Iron deficiency and malaria have similar global distributions, and frequently co-exist in pregnant women and young children. Where both conditions are prevalent, iron supplementation is complicated by observations that iron deficiency anaemia protects against falciparum malaria, and that iron supplements increase susceptibility to clinically significant malaria, but the mechanisms remain obscure. Here, using an in vitro parasite culture system with erythrocytes from iron-deficient and replete human donors, we demonstrate that Plasmodium falciparum infects iron-deficient erythrocytes less efficiently. In addition, owing to merozoite preference for young erythrocytes, iron supplementation of iron-deficient individuals reverses the protective effects of iron deficiency. Our results provide experimental validation of field observations reporting protective effects of iron deficiency and harmful effects of iron administration on human malaria susceptibility. Because recovery from anaemia requires transient reticulocytosis, our findings imply that in malarious regions iron supplementation should be accompanied by effective measures to prevent falciparum malaria.

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“…[12][13][14][15] Iron deficiency also provides protection against infection with Plasmodium berghei in mice. 16,17 M alaria, a major global health challenge worldwide, is accompanied by a severe anemia secondary to hemolysis and increased erythrophagocytosis. Iron is an essential functional component of erythrocyte hemoglobin and its availability is controlled by the liverderived hormone hepcidin.…”

Section: Introductionmentioning

confidence: 99%

Erythroferrone contributes to hepcidin repression in a mouse model of malarial anemia

et al. 2016

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A critical role for phagocytosis in resistance to malaria in iron‐deficient mice

Cited by 23 publications

References 31 publications

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

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

Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum

Erythroferrone contributes to hepcidin repression in a mouse model of malarial anemia

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