Ring-stage growth arrest: Metabolic basis of artemisinin tolerance in Plasmodium falciparum
Summary: The emergence and spread of artemisinin-tolerant malaria parasites threatens malaria control programmes worldwide. Mutations in the propeller domain of the Kelch13 protein confer Plasmodium falciparum artemisinin resistance (ART-R). ART-R is linked to the reduced susceptibility of temporary...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222019988 |
| _version_ | 1797946156064440320 |
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| author | Xinyu Yu Changhong Wang Yuemeng Zhao Jianxia Tang Meng Zhu Lucien Platon Richard Culleton Guoding Zhu Didier Ménard Qingfeng Zhang Jun Cao |
| author_facet | Xinyu Yu Changhong Wang Yuemeng Zhao Jianxia Tang Meng Zhu Lucien Platon Richard Culleton Guoding Zhu Didier Ménard Qingfeng Zhang Jun Cao |
| author_sort | Xinyu Yu |
| collection | DOAJ |
| description | Summary: The emergence and spread of artemisinin-tolerant malaria parasites threatens malaria control programmes worldwide. Mutations in the propeller domain of the Kelch13 protein confer Plasmodium falciparum artemisinin resistance (ART-R). ART-R is linked to the reduced susceptibility of temporary growth-arrested ring-stage parasites, but the metabolic mechanisms remain elusive. We generated two PfKelch13 mutant lines via CRISPR-Cas9 gene editing which displayed a reduced susceptibility accompanied by an extended ring stage. The metabolome of ART-induced ring-stage growth arrest parasites carrying PfKelch13 mutations showed significant alterations in the tricarboxylic acid (TCA) cycle, glycolysis, and amino acids metabolism, pointing to altered energy and porphyrin metabolism with metabolic plasticity. The critical role of these pathways was further confirmed by altering metabolic flow or through chemical inhibition. Our findings uncover that the growth arrestment associated with ART-R is potentially attributed to the adaptative metabolic plasticity, indicating that the defined metabolic remodeling turns out to be the trigger for ART-R. |
| first_indexed | 2024-04-10T21:06:25Z |
| format | Article |
| id | doaj.art-5a9f6bb0af1440b0920a6dd0af6e70e4 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-10T21:06:25Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-5a9f6bb0af1440b0920a6dd0af6e70e42023-01-22T04:40:34ZengElsevieriScience2589-00422023-01-01261105725Ring-stage growth arrest: Metabolic basis of artemisinin tolerance in Plasmodium falciparumXinyu Yu0Changhong Wang1Yuemeng Zhao2Jianxia Tang3Meng Zhu4Lucien Platon5Richard Culleton6Guoding Zhu7Didier Ménard8Qingfeng Zhang9Jun Cao10Medical College of Soochow University, Suzhou, China; National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, China; Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, ChinaLaboratory of Molecular Parasitology, Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital; Clinical Center for Brain and Spinal Cord Research, School of Medicine, Tongji University, Shanghai 200092, ChinaLaboratory of Molecular Parasitology, Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital; Clinical Center for Brain and Spinal Cord Research, School of Medicine, Tongji University, Shanghai 200092, ChinaNational Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, China; Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, ChinaCenter for Global Health, School of Public Health, Nanjing Medical University, Nanjing, ChinaInstitut Pasteur, Université Paris Cité, INSERM U1201, Malaria Genetics and Resistance Unit, 75015 Paris, France; Sorbonne Université, Ecole Doctorale ED515 Complexité du Vivant, 75005 Paris, FranceDivision of Molecular Parasitology, Proteo-Science Centre, Ehime University, Matsuyama, Ehime 790-8577, JapanNational Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, China; Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China; Corresponding authorInstitut Pasteur, Université Paris Cité, INSERM U1201, Malaria Genetics and Resistance Unit, 75015 Paris, France; Institute of Parasitology and Tropical Diseases, UR7292 Dynamics of Host-Pathogen Interactions, Federation of Translational Medicine, University of Strasbourg, Strasbourg, France; Laboratory of Parasitology and Medical Mycology, Strasbourg University Hospital, Strasbourg, France; Corresponding authorLaboratory of Molecular Parasitology, Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital; Clinical Center for Brain and Spinal Cord Research, School of Medicine, Tongji University, Shanghai 200092, China; Corresponding authorNational Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, China; Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China; Corresponding authorSummary: The emergence and spread of artemisinin-tolerant malaria parasites threatens malaria control programmes worldwide. Mutations in the propeller domain of the Kelch13 protein confer Plasmodium falciparum artemisinin resistance (ART-R). ART-R is linked to the reduced susceptibility of temporary growth-arrested ring-stage parasites, but the metabolic mechanisms remain elusive. We generated two PfKelch13 mutant lines via CRISPR-Cas9 gene editing which displayed a reduced susceptibility accompanied by an extended ring stage. The metabolome of ART-induced ring-stage growth arrest parasites carrying PfKelch13 mutations showed significant alterations in the tricarboxylic acid (TCA) cycle, glycolysis, and amino acids metabolism, pointing to altered energy and porphyrin metabolism with metabolic plasticity. The critical role of these pathways was further confirmed by altering metabolic flow or through chemical inhibition. Our findings uncover that the growth arrestment associated with ART-R is potentially attributed to the adaptative metabolic plasticity, indicating that the defined metabolic remodeling turns out to be the trigger for ART-R.http://www.sciencedirect.com/science/article/pii/S2589004222019988Multidrug resistant organismsParasitology |
| spellingShingle | Xinyu Yu Changhong Wang Yuemeng Zhao Jianxia Tang Meng Zhu Lucien Platon Richard Culleton Guoding Zhu Didier Ménard Qingfeng Zhang Jun Cao Ring-stage growth arrest: Metabolic basis of artemisinin tolerance in Plasmodium falciparum iScience Multidrug resistant organisms Parasitology |
| title | Ring-stage growth arrest: Metabolic basis of artemisinin tolerance in Plasmodium falciparum |
| title_full | Ring-stage growth arrest: Metabolic basis of artemisinin tolerance in Plasmodium falciparum |
| title_fullStr | Ring-stage growth arrest: Metabolic basis of artemisinin tolerance in Plasmodium falciparum |
| title_full_unstemmed | Ring-stage growth arrest: Metabolic basis of artemisinin tolerance in Plasmodium falciparum |
| title_short | Ring-stage growth arrest: Metabolic basis of artemisinin tolerance in Plasmodium falciparum |
| title_sort | ring stage growth arrest metabolic basis of artemisinin tolerance in plasmodium falciparum |
| topic | Multidrug resistant organisms Parasitology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222019988 |
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