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

Abstract

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.

Keywords: CP: Metabolism; CP: Microbiology; PRDX6; Plasmodium falciparum; artemisinin; endocytosis; hemoglobin; host cell cytosol uptake; lipid peroxidation; malaria; molecular parasitology; oxidative stress.