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

• Main Authors: 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., Ménard, Didier, Bozdech, Zbynek, Amino, Rogerio, Touqui, Lhousseine, Chitnis, Chetan E.
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2023
• Subjects: Science::Biological sciences; Artemisinin; Endocytosis
• Online Access: https://hdl.handle.net/10356/164886
• Institution: Nanyang Technological University

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.