Host iron deficiency protects against Plasmodium infection and drives parasite molecular reprofiling.

Iron deficiency, anemia and Plasmodium infection represent significant global health challenges with overlapping geographical distributions, particularly affecting pregnant women in Africa, yet the mechanisms underlying their interactions remain poorly understood. We employed a multilayered approach combining clinical data from Malawian pregnant women (n=711) in the REVAMP trial, a genetic mouse model (Tmprss6-knockout), and in vitro P. falciparum cultures to clarify associations between iron status and malaria susceptibility. Iron deficiency was associated with 50% reduced P. falciparum parasitemia in pregnant women (95% CI [30%-64%], p<0.0001), while iron-deficient mice exhibited significantly improved survival against P. berghei (median 15.5 days vs. 7.0 days for WT mice) and protection from cerebral malaria (83% vs 17% survival). Iron chelation induced substantial transcriptomic and proteomic changes in cultured parasites, affecting host cell invasion and nutrient acquisition processes. Importantly, intravenous iron supplementation did not increase subsequent parasitemia when coupled with malaria prevention. These findings demonstrate that iron deficiency protects against Plasmodium infection and support WHO recommendations for iron supplementation in malaria-endemic regions when combined with adequate malaria prevention strategies.