Host iron deficiency protects against <i>Plasmodium</i> infection and drives parasite molecular reprofiling
Iron deficiency, anemia, and <i>Plasmodium</i> infection 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 (<i>n</i> = 711) in the REVAMP trial, a genetic mouse model [<i>Tmprss6</i>-knockout (KO)], and in vitro <i>Plasmodium falciparum</i> cultures to clarify iron-malaria associations. Iron deficiency was associated with 50% reduced <i>P. falciparum</i> parasitemia in pregnant women [95% CI (30 to 64%), <i>P</i> < 0.0001], while iron-deficient mice exhibited improved survival against <i>P. berghei</i> (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 cultured <i>P. falciparum</i> parasites. Intravenous iron supplementation did not increase parasitemia when coupled with malaria prevention. These findings demonstrate that iron deficiency protects against <i>Plasmodium</i> infection and support World Health Organization recommendations for iron supplementation in malaria-endemic regions when combined with adequate malaria prevention strategies in place.
Authors
- Glory Mzembe (ORCID: https://orcid.org/0000-0002-7277-9987)
- Louise M. Randall (ORCID: https://orcid.org/0009-0002-0391-1080)
- Daniela Amann‐Zalcenstein (ORCID: https://orcid.org/0000-0003-4928-1846)
- Martin N. Mwangi (ORCID: https://orcid.org/0000-0002-8358-4448)
- Anne Pettikiriarachchi
- Ronan Mellin (ORCID: https://orcid.org/0000-0002-4567-0660)
- Cavan Bennett (ORCID: https://orcid.org/0000-0002-9796-9381)
- Katherine Fielding (ORCID: https://orcid.org/0000-0002-6524-3754)
- Tracey M. Baldwin (ORCID: https://orcid.org/0000-0002-8919-5822)
- Andrew Baldi (ORCID: https://orcid.org/0000-0003-2581-1718)
- Danielle Clucas
- Rebecca Harding (ORCID: https://orcid.org/0000-0003-4267-716X)
- Sabine Braat (ORCID: https://orcid.org/0000-0003-1997-3999)
- Melissa S. Hobbs (ORCID: https://orcid.org/0000-0002-1846-1521)
- Sabrina Caiazzo
- Justin A. Boddey (ORCID: https://orcid.org/0000-0001-7322-2040)
- Aaron R. Jex (ORCID: https://orcid.org/0000-0002-1285-7947)
- Ernest Moya
- Ryan Steel (ORCID: https://orcid.org/0000-0002-4802-2896)
- Peter F. Hickey (ORCID: https://orcid.org/0000-0002-8153-6258)
- Samantha Emery-Corbin
- Ricardo Luis da Rocha ATAÍDE
- Sant-Rayn Pasricha
- Beverley-Ann Biggs
- Wai-Hong Tham
- Ayse Y. Demir
- Kamija S. Phiri
Institutions
- Australian National University (AU)
- Micron (United States) (US)
- The Royal Melbourne Hospital (AU)
- University of Malawi (MW)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Kamuzu Central Hospital (MW)
- Peter Doherty Institute (AU)
- Blantyre Institute for Community Ophthalmology (MW)
- Healthy Start (US)
- Meander Medisch Centrum (NL)
- Monash University (AU)
- Wageningen University & Research (NL)
Publication Details
- Journal
- Science Advances
- Published
- 2026-02-27
- DOI
- https://doi.org/10.1126/sciadv.aeb0828
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 0.00