MODULATION OF HOST IRON COMPARTMENTS CRITICAL TO THE MALARIA PARASITE DEVELOPMENT

The overlap between of malaria and iron deficiency makes it difficult to treat both conditions since iron supplementation can increase malaria and malaria decreases iron absorption. Iron chelators have proven antiparasitic activity. We characterized the antimalarial pharmacodynamics of the novel iron chelator FBS0701 in Plasmodium and evaluated the effect of the type and timing of iron diet on murine malaria during iron repletion. FBS0701, (S)3’’-(HO)-desazadesferrithiocin-polyether [DADFT-PE], is an oral iron chelator to treat transfusional iron overload. We showed that FBS0701 enter the erythrocytes and removes intracellular iron. FBS0701 reduced hepatic parasite load. FBS0701 interfered with artemisinin but was additive with chloroquine or quinine inhibition in the blood stage and with primaquine in the hepatic stage. FBS0701 killed early and late stage P. falciparum gametocytes. A single oral dose one day after infection cured P. yoelii 17XL infected mice. We studied the importance of iron compartmentalization on hepatic malaria infection on transgenic anemic mice: mice overexpressing hepcidin with reduced iron stores in the liver and hemoglobin deficient mice with normal hepatic iron stores. We found lower parasites on mice overexpressing hepcidin compared to non-anemic control mice (with normal liver iron). Parasite loads on hemoglobin deficient mice were not significantly different to non-anemic control mice. Finally, we studied the effect of low and high iron diets on the hepatic stage of murine malaria and the interplay of hepcidin with the hepatic infection levels. We used mice that were both anemic and iron deficient as well as non-anemic mice and gave both groups low and high iron diets for 2 and 6 weeks. Our results showed that high iron diets increased liver stage parasites in non-anemic mice and that iron supplementation predominated over a negative hepcidin effect. We partially replicated in mice the human findings from the Pemba study. In conclusion, FBS0701 could be useful as malarial prophylactic or in combination with other antimalarials. FBS0701 has the potential to be used a transmission blocking agent. Increasing liver stage may synergize with blood stage increases after iron supplementation. Therefore, iron supplementation programs in malaria endemic areas, should be accompanied of antimalarial treatment