Journal
SCIENCE
Volume 359, Issue 6383, Pages 1520-1523Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aal2022
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Funding
- intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Division of Intramural Research at the National Institute of Allergy and Infectious Diseases (NIAID), NIH
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Malaria parasites invade red blood cells (RBCs), consume copious amounts of hemoglobin, and severely disrupt iron regulation in humans. Anemia often accompanies malaria disease; however, iron supplementation therapy inexplicably exacerbates malarial infections. Here we found that the iron exporter ferroportin (FPN) was highly abundant in RBCs, and iron supplementation suppressed its activity. Conditional deletion of the Fpn gene in erythroid cells resulted in accumulation of excess intracellular iron, cellular damage, hemolysis, and increased fatality in malaria-infected mice. In humans, a prevalent FPN mutation, Q248H (glutamine to histidine at position 248), prevented hepcidin-induced degradation of FPN and protected against severe malaria disease. FPN Q248H appears to have been positively selected in African populations in response to the impact of malaria disease. Thus, FPN protects RBCs against oxidative stress and malaria infection.
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