Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target
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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Online Access: | https://hdl.handle.net/10356/164886 |
| _version_ | 1811682417978638336 |
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| author | 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. |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences 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. |
| author_sort | Wagner, Matthias Paulus |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T03:56:31Z |
| format | Journal Article |
| id | ntu-10356/164886 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:56:31Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1648862023-02-28T17:14:12Z Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target 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. School of Biological Sciences Science::Biological sciences Artemisinin Endocytosis 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. 2023-02-22T03:33:50Z 2023-02-22T03:33:50Z 2022 Journal Article Wagner, M. P., Formaglio, P., Gorgette, O., Dziekan, J. M., Huon, C., Berneburg, I., Rahlfs, S., Barale, J., Feinstein, S. I., Fisher, A. B., Ménard, D., Bozdech, Z., Amino, R., Touqui, L. & Chitnis, C. E. (2022). Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target. Cell Reports, 39(11), 110923-. https://dx.doi.org/10.1016/j.celrep.2022.110923 2211-1247 https://hdl.handle.net/10356/164886 10.1016/j.celrep.2022.110923 35705035 2-s2.0-85131969333 11 39 110923 en NTU/PPF/2019 MOE-T2EP30120-0015 Cell Reports © 2022 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). application/pdf |
| spellingShingle | Science::Biological sciences Artemisinin Endocytosis 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. Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target |
| title | Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target |
| title_full | Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target |
| title_fullStr | Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target |
| title_full_unstemmed | Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target |
| title_short | Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target |
| title_sort | human peroxiredoxin 6 is essential for malaria parasites and provides a host based drug target |
| topic | Science::Biological sciences Artemisinin Endocytosis |
| url | https://hdl.handle.net/10356/164886 |
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