Cellular iron governs the host response to malaria

Wideman, Sarah K.; Frost, Joe N.; Richter, Felix C.; Naylor, Caitlin; Lopes, José M.; Viveiros, Nicole; Teh, Megan R.; Preston, Alexandra E.; White, Natasha; Yusuf, Shamsideen; Draper, Simon J.; Armitage, Andrew E.; Duarte, Tiago L.; Drakesmith, Hal

doi:10.1371/journal.ppat.1011679

Cited by 7 publications

(4 citation statements)

References 88 publications

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“…Intracellular iron concentration is a complex balance, and sufficient iron supply enhances Plasmodium clearance through ferroptosis pathway and restoration of immune cell function. However, this may also lead to excessive immune damage [11]. Based on the typical usage of ACTs and iron supplements, we determined the daily dosage of artemisinin-based combinations with different iron supplements for mice.…”

Section: Discussionmentioning

confidence: 99%

Addressing Artemisinin Resistance in Malaria Treatment: A Novel Ferrous ACT (FACT) Formulation

Wang,

Tang

2024

Preprint

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Malaria is the worldwide infectious disease causing significant losses of human lives every year. The deployment of artemisinin-based combination therapies (ACTs) has helped to reduce the losses caused by malaria. However, resistance to ACTs evolved especially by Plasmodium falciparum occurs and becomes more and more threats for human lives. Up to now, there is no effective way to solve this drug-resistance problem. Here we propose a new ACT, which contains traditional ACT plus iron supplement, so-called ferrous ACT (FACT). The FACT is promising to become a safe and effective new formulation to combat ACT resistance malaria, helping WHO reach its 2030's Malaria Control Goal.

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Section: Discussionmentioning

confidence: 99%

Addressing Artemisinin Resistance in Malaria Treatment: A Novel Ferrous ACT (FACT) Formulation

Wang,

Tang

2024

Preprint

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“…This latter hypothesis is consistent with a recent study demonstrating attenuated hepatic immune response and reduced hepatic pathology in P. chabaudi -infected transgenic mice carrying a mutation in the transferrin receptor causing decreased cellular iron uptake. 42…”

Section: Discussionmentioning

confidence: 99%

Longitudinal changes in iron homeostasis in human experimental and clinical malaria

Woolley,

Grigg,

Marquart

et al. 2023

Preprint

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BackgroundThe interaction between iron deficiency and malaria is incompletely understood. We evaluated longitudinal changes in iron homeostasis in volunteers enrolled in malaria volunteer infection studies (VIS) and in Malaysian patients with falciparum and vivax malaria.MethodsWe retrieved samples and associated data from 55 participants enrolled in malaria VIS, and 171 malaria patients and 30 healthy controls enrolled in clinical studies in Malaysia. Ferritin, hepcidin, erythropoietin, and soluble transferrin receptor (sTfR) were measured by ELISA.ResultsIn the VIS, participants’ parasitaemia was correlated with baseline mean corpuscular volume (MCV), but not iron status (ferritin, hepcidin or sTfR). Ferritin, hepcidin and sTfR all increased during the VIS. Ferritin and hepcidin normalised by day 28, while sTfR remained elevated. In VIS participants, baseline iron status (ferritin) was associated with post-treatment increases in liver transaminase levels. In Malaysian malaria patients, hepcidin and ferritin were elevated on admission compared to healthy controls, while sTfR increased following admission. Hepcidin normalised by day 28; however, ferritin and sTfR both remained elevated 4 weeks following admission.ConclusionOur findings demonstrate that parasitaemia is associated with an individual’s MCV rather than iron status. The persistent elevation in sTfR 4 weeks post-infection in both malaria VIS and clinical malaria may reflect a causal link between malaria and iron deficiency.

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“…7b, q=0.006) observed herein. Lung B and T cells are well described for COVID-19 [147, 148]; however, iron deficiency is generally associated with impaired B and T cell responses [149, 150]. The Interstitial macrophages are generally anti-inflammatory during disease processes [151] and Ear2 is upregulated on alveolar macrophages under Th2 conditions [152], so reduced abundance scores for these two cell types in iron deficient mice (Fig.…”

Section: Iron Deficient Vs Control Diet; Lung Rna-seq At 6 Dpimentioning

confidence: 99%

The effects of iron deficient and high iron diets on SARS-CoV-2 lung infection and disease

Carolin,

Frazer,

Yan

et al. 2024

Preprint

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The severity of Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is often dictated by a range of comorbidities. A considerable literature suggests iron deficiency and iron overload may contribute to increased infection, inflammation and disease severity, although direct causal relationships have been difficult to establish. Here we generate iron deficient and iron loaded C57BL/6J mice by feeding low and high iron diets, with mice on a normal iron diet representing controls. All mice were infected with a primary omicron XXB SARS-CoV-2 isolate and lung inflammatory responses were analyzed by histology, immunohistochemistry and RNA-Seq. Compared with controls, iron deficient mice showed no significant changes in lung viral loads or histopathology, whereas, iron loaded mice showed slightly, but significantly, reduced lung viral loads and histopathology. Transcriptional changes were modest, but illustrated widespread dysregulation of inflammation signatures for both iron deficient vs. controls, and iron loaded vs. controls. Some of these changes could be associated with detrimental outcomes, whereas others would be viewed as beneficial. Diet-associated iron deficiency or overload thus induced modest modulations of inflammatory signatures, but no significant histopathologically detectable disease exacerbations.Author summaryA diet deficient in iron can lead to anemia, a widespread problem worldwide. A diet with excessive iron is less common, but can be associated with excessive consumption of iron supplements. We investigate herein using a mouse model, whether low or high iron diets predispose to detrimental outcomes in the lungs after infection with SARS-CoV-2. A considerable literature suggests iron dysregulation would promote infection and inflammation. However, we found, although inflammatory responses showed modest modulations, viral loads were unaffected or slightly reduced, and lung histopathology was either unaffected or indicated slightly less severe disease. These findings do not support a view that low or high iron diets represent comorbidities predisposing to overt detrimental outcomes for acute COVID-19 lung disease.

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Cellular iron governs the host response to malaria

Cited by 7 publications

References 88 publications

Addressing Artemisinin Resistance in Malaria Treatment: A Novel Ferrous ACT (FACT) Formulation

Addressing Artemisinin Resistance in Malaria Treatment: A Novel Ferrous ACT (FACT) Formulation

Longitudinal changes in iron homeostasis in human experimental and clinical malaria

The effects of iron deficient and high iron diets on SARS-CoV-2 lung infection and disease

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