Host iron deficiency protects against Plasmodium infection and drives parasite molecular reprofiling
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Background
Iron deficiency, anemia and Plasmodium infection represent significant global health challenges with overlapping geographical distributions, particularly affecting pregnant women in Africa. Previous evidence suggests complex interactions between iron status and malaria susceptibility. However, the mechanisms and clinical implications of this relationship remain poorly understood.
Methods
We employed a multilayered integrated approach to clarify the association between iron deficiency and malaria infection risk. First, we analyzed clinical data from Malawian pregnant women (n=711) participating in the REVAMP clinical trial—an RCT of intravenous iron versus oral iron—to assess associations between iron status and P. falciparum parasitemia detected by ultra-sensitive qPCR. All eligible women received intermittent preventive anti-malaria treatment. Then, we utilized a genetic mouse model ( Tmprss6 -knockout) to isolate the effect of iron deficiency on P. berghei infection and progression to clinical disease. Finally, we explored direct effects of iron chelation on cultured P. falciparum parasites through transcriptomic and proteomic analyses.
Results
In REVAMP, iron deficiency was associated with a 50% reduced probability of P. falciparum qPCR positivity at baseline (95% CI [30%-64%], p<0.0001). Iron intervention given at baseline did not significantly modify the probability of subsequent parasitemia across the pregnancy. In the murine model, iron-deficient Tmprss6 -knockout mice exhibited significantly improved survival compared to controls (median survival 15.5 vs. 7.0 days) and protection from cerebral malaria (survival 83% vs 17%). Iron chelation in P. falciparum cultures induced substantial transcriptomic (1,397 differentially expressed genes) and proteomic changes (121 differentially expressed proteins; 46 matched differentially expressed gene/protein pairs), primarily affecting processes involved in host cell invasion, protein export, and nutrient acquisition.
Conclusion
Our findings consistently demonstrate that iron deficiency protects against Plasmodium infection across clinical, pre-clinical, and in vitro models. Importantly, in the presence of adequate malaria prevention intravenous iron supplementation did not significantly increase subsequent parasitemia prevalence. These results provide mechanistic insights into iron and malaria interactions and support current WHO recommendations for iron supplementation in pregnant women in malaria-endemic regions when coupled with adequate malaria prevention strategies.
Funding
Bill and Melinda Gates Foundation, National Health and Medical Research Council of Australia, and the Victorian State Government Operational Infrastructure Support.
