Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target

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Wagner, Matthias Paulus | Formaglio, Pauline | Gorgette, Olivier | Dziekan, Jerzy Michal | Huon, Christèle | Berneburg, Isabell | Rahlfs, Stefan | Barale, Jean-Christophe | Feinstein, Sheldon, I | Fisher, Aron, B | Menard, Didier | Bozdech, Zbynek | Amino, Rogerio | Touqui, Lhousseine | Chitnis, Chetan, E

Edité par CCSD ; Elsevier Inc -

International audience. The uptake and digestion of host hemoglobin by malaria parasites during blood-stage growth leads to significant oxidative damage of membrane lipids. Repair of lipid peroxidation damage is crucial for parasite survival. Here, we demonstrate that Plasmodium falciparum imports a host antioxidant enzyme, peroxiredoxin 6 (PRDX6), during hemoglobin uptake from the red blood cell cytosol. PRDX6 is a lipid-peroxidation repair enzyme with phospholipase A2 (PLA2) activity. Inhibition of PRDX6 with a PLA2 inhibitor, Darapladib, increases lipid-peroxidation damage in the parasite and disrupts transport of hemoglobin-containing vesicles to the food vacuole, causing parasite death. Furthermore, inhibition of PRDX6 synergistically reduces the survival of artemisinin-resistant parasites following co-treatment of parasite cultures with artemisinin and Darapladib. Thus, PRDX6 is a host-derived drug target for development of antimalarial drugs that could help overcome artemisinin resistance.

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