title: Drug resistance. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance.
abstract: Artemisinin resistance in Plasmodium falciparum threatens global efforts to control and eliminate malaria. Polymorphisms in the kelch domain-carrying protein K13 are associated with artemisinin resistance, but the underlying molecular mechanisms are unknown. We analyzed the in vivo transcriptomes of 1043 P. falciparum isolates from patients with acute malaria and found that artemisinin resistance is associated with increased expression of unfolded protein response (UPR) pathways involving the major PROSC and TRiC chaperone complexes. Artemisinin-resistant parasites also exhibit decelerated progression through the first part of the asexual intraerythrocytic development cycle. These findings suggest that artemisinin-resistant parasites remain in a state of decelerated development at the young ring stage, whereas their up-regulated UPR pathways mitigate protein damage caused by artemisinin. The expression profiles of UPR-related genes also associate with the geographical origin of parasite isolates, further suggesting their role in emerging artemisinin resistance in the Greater Mekong Subregion.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Sachel
authors.initials: S
authors.lastname: Mok
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Ashley
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Pedro E
authors.initials: PE
authors.lastname: Ferreira
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Zhaoting
authors.initials: Z
authors.lastname: Lin
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Tomas
authors.initials: T
authors.lastname: Yeo
authors.affiliation: Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Kesinee
authors.initials: K
authors.lastname: Chotivanich
authors.affiliation: Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Mallika
authors.initials: M
authors.lastname: Imwong
authors.affiliation: Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Sasithon
authors.initials: S
authors.lastname: Pukrittayakamee
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. WorldWide Antimalarial Resistance Network (WWARN), Asia Regional Centre, Mahidol University, Bangkok, Thailand. WorldWide Antimalarial Resistance Network, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Mehul
authors.initials: M
authors.lastname: Dhorda
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Chea
authors.initials: C
authors.lastname: Nguon
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Pharath
authors.initials: P
authors.lastname: Lim
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Chanaki
authors.initials: C
authors.lastname: Amaratunga
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Seila
authors.initials: S
authors.lastname: Suon
authors.affiliation: Oxford University Clinical Research Unit (OUCRU), Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Tran Tinh
authors.initials: TT
authors.lastname: Hien
authors.affiliation: Department of Medical Research, Lower Myanmar, Yangon, Myanmar.
authors.forename: Ye
authors.initials: Y
authors.lastname: Htut
authors.affiliation: Malaria Research Group & Dev Care Foundation, Dhaka, Bangladesh.
authors.forename: M Abul
authors.initials: MA
authors.lastname: Faiz
authors.affiliation: Kinshasa School of Public Health, Kinshasa, Democratic Republic of the Congo.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Onyamboko
authors.affiliation: Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Mahosot Hospital, Vientiane, Lao PDR. Faculty of Postgraduate Studies, University of Health Sciences, Vientiane, Lao PDR.
authors.forename: Mayfong
authors.initials: M
authors.lastname: Mayxay
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Mahosot Hospital, Vientiane, Lao PDR.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Newton
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Rupam
authors.initials: R
authors.lastname: Tripura
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Woodrow
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Olivo
authors.initials: O
authors.lastname: Miotto
authors.affiliation: Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
authors.affiliation: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: François
authors.initials: F
authors.lastname: Nosten
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Preiser
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Fairhurst
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore. zbozdech@ntu.edu.sg.
authors.forename: Zbynek
authors.initials: Z
authors.lastname: Bozdech
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D056404:Chaperonin Containing TCP-1 / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics*; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics*; D059467:Transcriptome; D056811:Unfolded Protein Response / Q000235:genetics*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C031327:artemisinin; D056404:Chaperonin Containing TCP-1