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

Autor: 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
Přispěvatelé: Biologie de Plasmodium et Vaccins - Malaria Parasite Biology and Vaccines, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Infection et Immunité paludéennes - Malaria Infection and Immunity, Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Institut Pasteur [Paris] (IP), Nanyang Technological University [Singapour], Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Malaria Translational Research Unit (MTRU), Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut Pasteur [Paris] (IP), Perelman School of Medicine, University of Pennsylvania, Génétique du paludisme et résistance - Malaria Genetics and Resistance, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Dynamique des interactions Hôte pathogène, Université de Strasbourg (UNISTRA), Institut de Parasitologie et de Pathologie Tropicale (IPPTS), Mucoviscidose et bronchopathies chroniques : biopathologie et phénotype cliniques - Cystic Fibrosis and Bronchial Diseases, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Paris Cité (UPCité), This work was funded by the following grants: Fondation pour la Recherche Médicale grant (FDT202001010791) to M.P.W., Agence Nationale de la Recherche grant (ANR-17-CE15-0010) to C.E.C., Pasteur Innov grant from Institut Pasteur to C.E.C., Laboratoire d’Excellence (LabEx) 'French Parasitology Alliance For Health Care' (ANR-11-LABX-0024-PARAFRAP) to C.E.C. and D.M., Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant no. ANR-10-LABX-62-IBEID) to P.F., NTU Presidential Postdoctoral Fellowship grant (NTU/PPF/2019) to J.M.D., Singaporean Ministry of Education grant (MOE-T2EP30120-0015) to J.M.D. and Z.B., and LOEWE Center DRUID (Projects B3) within the Hessian Excellence Program to I.B., We thank Gordon Langsley for fruitful discussions and critical inputs. We also thank the electron microscopy Ultrastructural BioImaging (UBI) platform, Institut Pasteur, Paris, for providing ready access to the electron microscopy facility. The authors are grateful to the Central Animal Facility of Institut Pasteur for providing support with animal importation, care, housing, and breeding. We thank the Image Analysis Hub (IAH), Institut Pasteur, Paris, for their help with image analysis. M.P.W. was part of the Pasteur - Paris University (PPU) International PhD Program and European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 665807., ANR-17-CE15-0010,MolSigMal,Evènements moléculaires de la signalisation induite par l'invasion des globules rouges par les parasites paludéens(2017), ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 665807,H2020,H2020-MSCA-COFUND-2014,PASTEURDOC(2015), School of Biological Sciences
Rok vydání: 2022
Předmět:
Zdroj: Cell Reports
Cell Reports, 2022, 39 (11), pp.110923. ⟨10.1016/j.celrep.2022.110923⟩
ISSN: 2211-1247
Popis: 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. Ministry of Education (MOE) Nanyang Technological University Published version M.P.W. was part of the Pasteur - Paris University (PPU) International PhD Program and European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 665807. This work was funded by the following grants: Fondation pour la Recherche Me ́ dicale grant (FDT202001010791) to M.P.W.; Agence Nationale de la Recherche grant (ANR-17-CE15-0010) to C.E.C.; Pasteur Innov grant from Institut Pasteur to C.E.C.; Laboratoire d’Excellence (LabEx) ‘‘French Parasitology Alliance For Health Care’’ (ANR-11-LABX-0024-PARAFRAP) to C.E.C. and D.M.; Laboratoire d’Excellence ‘‘Integrative Biology of Emerging Infectious Diseases’’ (grant no. ANR-10-LABX-62-IBEID) to P.F.; NTU Presidential Postdoctoral Fellowship grant (NTU/PPF/2019) to J.M.D.; Singaporean Ministry of Education grant (MOE-T2EP30120-0015) to J.M.D. and Z.B.; and LOEWE Center DRUID (Projects B3) within the Hessian Excellence Program to I.B.
Databáze: OpenAIRE
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