Host iron deficiency protects againstinfection and drives parasite molecular reprofiling.

Abstract

Iron deficiency, anemia, andinfection are global health challenges with overlapping geographical distributions, particularly affecting pregnant women in Africa, yet the mechanisms underlying their interactions remain poorly understood. We used a multilayered approach combining clinical data from Malawian pregnant women (&#xa0;=&#xa0;711) in the REVAMP trial, a genetic mouse model [-knockout (KO)], and in vitrocultures to clarify iron-malaria associations. Iron deficiency was associated with 50% reducedparasitemia in pregnant women [95% CI (30 to 64%),&#xa0;<&#xa0;0.0001], while iron-deficient mice exhibited improved survival against(median 15.5 days versus 7.0 days for WT mice) and protection from cerebral malaria (83% versus 17% survival). Iron chelation substantially changed the transcriptomic and proteomic profile of culturedparasites. Intravenous iron supplementation did not increase parasitemia when coupled with malaria prevention. These findings demonstrate that iron deficiency protects againstinfection and support World Health Organization recommendations for iron supplementation in malaria-endemic regions when combined with adequate malaria prevention strategies in place.