MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
Kennedy Institute of Rheumatology, Roosevelt Drive, Oxford, United Kingdom.
PLoS Pathog. 2023 Oct 9;19(10):e1011679. doi: 10.1371/journal.ppat.1011679. eCollection 2023 Oct.
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.
疟疾和缺铁是全球主要的健康问题，它们在流行病学上有广泛的重叠。缺铁性贫血通过限制寄生虫生长来保护宿主免受疟疾的侵害。另一方面，缺铁会严重破坏免疫细胞的功能。然而，在疟疾中，宿主细胞缺铁除了导致贫血之外，对其他方面的影响仍然难以捉摸。为了解决这个问题，我们使用了一种携带转铁蛋白受体（TfrcY20H/Y20H）突变的转基因小鼠模型，该突变限制了细胞从血浆中内化铁的能力。在生理状态下，TfrcY20H/Y20H 小鼠看起来健康，不贫血。然而，感染伯氏疟原虫（Plasmodium chabaudi chabaudi AS）的 TfrcY20H/Y20H 小鼠表现出明显更高的峰值寄生虫血症和体重减轻。我们发现，TfrcY20H/Y20H 小鼠的疟疾诱导性贫血轨迹与野生型小鼠相似，循环铁的升高并没有增加峰值寄生虫血症。相反，感染伯氏疟原虫的 TfrcY20H/Y20H 小鼠的先天和适应性免疫反应受损，表现为细胞增殖和细胞因子产生减少。此外，我们证明这些免疫细胞损伤是细胞内固有缺陷，因为体外铁补充完全恢复了 CD4+T 细胞和 B 细胞的功能。尽管免疫反应受到抑制和寄生虫血症增加，TfrcY20H/Y20H 小鼠的肝脏损伤减轻，表现为寄生虫在肝脏中的滞留减少和肝脏免疫反应减弱。综上所述，这些结果表明，宿主细胞缺铁抑制免疫反应，但可防止疟疾感染期间肝组织的过度损伤。这些不同的影响揭示了铁在疟疾中保护和病理之间复杂平衡中的作用。
