Cellular iron governs the host response to malaria

• Type: Article in International Scientific Journal
• Date: 2023

Authors

Wideman, SK (Author) Other; Frost, JN (Author) Other; Richter, FC (Author) Other; Naylor, C (Author) Other; Lopes, JM (Author) FMUP; Viveiros, N (Author) Other; Teh, MR (Author) Other; Preston, AE (Author) Other; White, N (Author) Other; Yusuf, S (Author) Other; Draper, SJ (Author) Other; Armitage, AE (Author) Other; Duarte, TL (Author) Other; Drakesmith, H (Author) Other

Journal

Title: PLoS Pathogens

Vol. 19

ISSN: 1553-7366

Publisher: Public Library of Science

Indexing

ISI Web of Knowledge - 5 Citations

Scopus - 5 Citations

Other information

Authenticus ID: P-00X-W54

DOI: 10.1371/journal.ppat.1011679

Abstract (EN): 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 (TfrcY20H/Y20H), which limits the ability of cells to internalise iron from plasma. At homeostasis TfrcY20H/Y20H mice appear healthy and are not anaemic. However, TfrcY20H/Y20H mice infected with Plasmodium chabaudi chabaudi AS showed significantly higher peak parasitaemia and body weight loss. We found that TfrcY20H/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 TfrcY20H/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, TfrcY20H/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. Malaria is a serious and potentially lethal infectious disease that affects nearly 250 million people each year. It is caused by Plasmodium species parasites that are transmitted between humans by mosquitoes. Iron deficiency is prevalent in malaria endemic areas and there is a complex and incompletely understood relationship between iron and malaria. Although iron deficiency is known be protective in malaria, little is known about how iron deficiency affects host cells other than the red blood cells where Plasmodium replicates, such as immune, liver, lung or kidney cells. To address this, we used genetically modified mice with decreased cellular iron uptake, but no anaemia, and infected them with a mouse strain of malaria. These mice had a more severe infection, characterised by more infected red blood cells and more weight loss at the peak of infection compared to wild-type mice. Interestingly, the mice had a significantly weaker immune response but also less severe liver damage upon malaria infection, indicating a trade-off between pathogen control and host health. This study highlights the key role of host iron status in malaria and may have implications for the treatment approach to both malaria and iron deficiency in malaria endemic regions.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 26