Cellular iron governs the host response to malaria

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Abstract

Malaria and iron deficiency are major global health problems with extensive epidemiological overlap. Iron deficiency-induced anaemia can protect the host from malaria by limiting parasite growth. On the other hand, iron deficiency can significantly disrupt immune cell function. However, the impact of host cell iron scarcity beyond anaemia remains elusive in malaria. To address this, we employed a transgenic mouse model carrying a mutation in the transferrin receptor ( Tfrc Y20H/Y20H ), which limits the ability of cells to internalise iron from plasma. At homeostasis Tfrc Y20H/Y20H mice appear healthy and are not anaemic. However, Tfrc Y20H/Y20H mice infected with Plasmodium chabaudi chabaudi AS showed significantly higher peak parasitaemia and body weight loss. We found that Tfrc Y20H/Y20H mice displayed a similar trajectory of malaria-induced anaemia as wild-type mice, and elevated circulating iron did not increase peak parasitaemia. Instead, P . chabaudi infected Tfrc Y20H/Y20H mice had an impaired innate and adaptive immune response, marked by decreased cell proliferation and cytokine production. Moreover, we demonstrated that these immune cell impairments were cell-intrinsic, as ex vivo iron supplementation fully recovered CD4 + T cell and B cell function. Despite the inhibited immune response and increased parasitaemia, Tfrc Y20H/Y20H mice displayed mitigated liver damage, characterised by decreased parasite sequestration in the liver and an attenuated hepatic immune response. Together, these results show that host cell iron scarcity inhibits the immune response but prevents excessive hepatic tissue damage during malaria infection. These divergent effects shed light on the role of iron in the complex balance between protection and pathology in malaria.

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    Reply to the reviewers

    1. Point-by-point description of the revisions

    Reviewer #1

    Evidence, reproducibility and clarity (Required):

    In this paper by Wideman et al, the authors seek to determine the role of cellular iron homeostasis in the pathogenesis of murine malaria.

    The authors to attempt to disentangle the effects of anemia from that of cellular iron deficiency. The authors elegantly make use of a murine model of a rare human mutation in the transferrin receptor. This mutation leads to decreased receptor internalization and decreased cellular iron, but otherwise healthy mice. Using this model, the authors use a *P. chabaudi *infection model and show an increase in …

  2. Note: This preprint has been reviewed by subject experts for Review Commons. Content has not been altered except for formatting.

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    Referee #3

    Evidence, reproducibility and clarity

    Herein Wideman provide novel and important evidence on the role of iron availability for mounting an efficient immune response in a malaria infection model. They employed TfRC Y201H/Y201H mice which develop iron deficiency due to impaired cellular ingestion of transferrin bound iron. They found that those mice develop higher peak parasitemia after vector borne exposure to Pl. chabaudi chabaudi which was paralleled by an impaired immune response as reflected by altered CD4 cell activation, reduced IFN-g formation or reduced B-cell responsiveness. Those deficiencies could be re-covered upon ex vivo iron supplementation pointing to …

  3. Note: This preprint has been reviewed by subject experts for Review Commons. Content has not been altered except for formatting.

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    Referee #2

    Evidence, reproducibility and clarity

    In this manuscript, the authors have studied the role of iron deficiency in the host response to Plasmodium infection using a transgenic mouse model that carries a mutation in the transferrin receptor. They show that restricted cellular iron acquisition attenuated P. chabaudi infection- induced splenic and hepatic immune responses which in turn mitigated the immunopathology, even though the peak parasitemia was significantly high in the mutant mice. Interestingly, the course of parasite infection doesn't seem to be affected in the mutant mice compared to the wildtype mice despite the induction of poor immune responses. The authors …

  4. Note: This preprint has been reviewed by subject experts for Review Commons. Content has not been altered except for formatting.

    Learn more at Review Commons


    Referee #1

    Evidence, reproducibility and clarity

    In this paper by Wideman et al, the authors seek to determine the role of cellular iron homeostasis in the pathogenesis of murine malaria.

    The authors to attempt to disentangle the effects of anemia from that of cellular iron deficiency. The authors elegantly make use of a murine model of a rare human mutation in the transferrin receptor. This mutation leads to decreased receptor internalization and decreased cellular iron, but otherwise healthy mice. Using this model, the authors use a P. chabaudi infection model and show an increase in pathogen burden and a decrease in pathology. They show in some detail that the immune response …