Dynamic control of hepatic Plasmodium numbers by hepcidin despite elevated liver iron during iron supplementation

Treatment of iron deficiency anemia in malaria endemic areas is complicated as iron supplementation increases malaria risk while malaria decreases iron absorption. Here we measured the influence of hepcidin expression and non-heme iron during iron supplementation on hepatic Plasmodium berghei numbers in anemic and non-anemic mice. Despite elevated hepatic non-heme iron on the high iron diet, elevated hepcidin expression is associated with less parasite bioavailable iron and lower hepatic parasite loads in anemic, iron deficient mice after both two and six weeks of supplementation. A marginal trend to lower parasite hepatic numbers was seen in non-anemic, iron replete mice. In a transgenic model of severe anemia, mice with a deletion in Sec15l1, which reportedly have normal liver iron and normal hepcidin expression, there were no changes in liver parasite numbers or blood stage numbers or outcome in the lethal Plasmodium yoelii model. In summary during iron supplementation the lower hepatic malaria numbers are regulated more by hepcidin than the absolute level of non-heme hepatic iron.