Ring-stage growth arrest: Metabolic basis of artemisinin tolerance in Plasmodium falciparum
Xinyu Yu,
Changhong Wang,
Yuemeng Zhao,
Jianxia Tang,
Meng Zhu,
Lucien Platon,
Richard Culleton,
Guoding Zhu,
Didier Ménard,
Qingfeng Zhang,
Jun Cao
Affiliations
Xinyu Yu
Medical 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, China
Changhong Wang
Laboratory 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
Yuemeng Zhao
Laboratory 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
Jianxia Tang
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, China
Meng Zhu
Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
Lucien Platon
Institut Pasteur, Université Paris Cité, INSERM U1201, Malaria Genetics and Resistance Unit, 75015 Paris, France; Sorbonne Université, Ecole Doctorale ED515 Complexité du Vivant, 75005 Paris, France
Richard Culleton
Division of Molecular Parasitology, Proteo-Science Centre, Ehime University, Matsuyama, Ehime 790-8577, Japan
Guoding Zhu
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, China; Corresponding author
Didier Ménard
Institut 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 author
Qingfeng Zhang
Laboratory 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 author
Jun Cao
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, China; Corresponding author
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.
