Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target
Matthias Paulus Wagner,
Pauline Formaglio,
Olivier Gorgette,
Jerzy Michal Dziekan,
Christèle Huon,
Isabell Berneburg,
Stefan Rahlfs,
Jean-Christophe Barale,
Sheldon I. Feinstein,
Aron B. Fisher,
Didier Ménard,
Zbynek Bozdech,
Rogerio Amino,
Lhousseine Touqui,
Chetan E. Chitnis
Affiliations
Matthias Paulus Wagner
Institut Pasteur, Université de Paris, Malaria Parasite Biology and Vaccines Unit, Paris, France
Pauline Formaglio
Institut Pasteur, Université de Paris, Malaria Infection and Immunity Unit, Paris, France
Olivier Gorgette
Institut Pasteur, Department of Cell Biology and Infection, Centre for Innovation and Technological Research, Ultrastructural Bioimaging Unit, Paris, France
Jerzy Michal Dziekan
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
Christèle Huon
Institut Pasteur, Université de Paris, Malaria Parasite Biology and Vaccines Unit, Paris, France
Isabell Berneburg
Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen, Giessen, Germany
Stefan Rahlfs
Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen, Giessen, Germany
Jean-Christophe Barale
Institut Pasteur, Université de Paris, CNRS UMR 3528, Structural Microbiology Unit, Paris, France; Institut Pasteur, Pasteur International Unit, Pasteur International Network, Malaria Translational Research Unit, Phnom Penh, Cambodia and Paris, France
Sheldon I. Feinstein
Peroxitech, Inc., Philadelphia, PA, USA
Aron B. Fisher
Peroxitech, Inc., Philadelphia, PA, USA; Institute for Environmental Medicine, Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Didier Ménard
Institut Pasteur, Université de Paris, INSERM U1201, Malaria Genetics and Resistance Unit, Paris, France; Dynamics of Host-Pathogen Interactions, EA 7292, IPPTS, Strasbourg University, Strasbourg, France
Zbynek Bozdech
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
Rogerio Amino
Institut Pasteur, Université de Paris, Malaria Infection and Immunity Unit, Paris, France
Lhousseine Touqui
Cystic Fibrosis, Physiopathology and Phenogenomics, INSERM Unit 938, Saint-Antoine, Paris, France; Institut Pasteur, Université de Paris, Laboratory of Cystic Fibrosis and Chronic Bronchopathies, Paris, France
Chetan E. Chitnis
Institut Pasteur, Université de Paris, Malaria Parasite Biology and Vaccines Unit, Paris, France; Corresponding author
Summary: 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.
