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

doi:10.1016/j.celrep.2022.110923

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

Cell Rep. 2022 Jun 14;39(11):110923. doi: 10.1016/j.celrep.2022.110923.

Authors

Affiliations

¹ Institut Pasteur, Université de Paris, Malaria Parasite Biology and Vaccines Unit, Paris, France.
² Institut Pasteur, Université de Paris, Malaria Infection and Immunity Unit, Paris, France.
³ Institut Pasteur, Department of Cell Biology and Infection, Centre for Innovation and Technological Research, Ultrastructural Bioimaging Unit, Paris, France.
⁴ School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
⁵ Biochemistry and Molecular Biology, Interdisciplinary Research Centre, Justus Liebig University Giessen, Giessen, Germany.
⁶ 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.
⁷ Peroxitech, Inc., Philadelphia, PA, USA.
⁸ Peroxitech, Inc., Philadelphia, PA, USA; Institute for Environmental Medicine, Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁹ 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.
¹⁰ 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.
¹¹ Institut Pasteur, Université de Paris, Malaria Parasite Biology and Vaccines Unit, Paris, France. Electronic address: [email protected].

PMID: 35705035
DOI: 10.1016/j.celrep.2022.110923

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antimalarials* / pharmacology
Artemisinins* / metabolism
Artemisinins* / pharmacology
Benzaldehydes / pharmacology
Drug Resistance
Hemoglobins / metabolism
Humans
Lipids
Malaria* / drug therapy
Malaria, Falciparum* / drug therapy
Malaria, Falciparum* / parasitology
Mice
Oximes / pharmacology
Peroxiredoxin VI* / immunology
Peroxiredoxin VI* / metabolism
Plasmodium falciparum

Substances

Antimalarials
Artemisinins
Benzaldehydes
Hemoglobins
Lipids
Oximes
Peroxiredoxin VI
darapladib