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Science. 2015 Jan 23;347(6220):431-5. doi: 10.1126/science.1260403. Epub 2014 Dec 11.

Drug resistance. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance.

Author information

1
School of Biological Sciences, Nanyang Technological University, Singapore.
2
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.
3
Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
4
Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
5
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.
6
National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
7
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.
8
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
9
Oxford University Clinical Research Unit (OUCRU), Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
10
Department of Medical Research, Lower Myanmar, Yangon, Myanmar.
11
Malaria Research Group & Dev Care Foundation, Dhaka, Bangladesh.
12
Kinshasa School of Public Health, Kinshasa, Democratic Republic of the Congo.
13
Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Mahosot Hospital, Vientiane, Lao PDR. Faculty of Postgraduate Studies, University of Health Sciences, Vientiane, Lao PDR.
14
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.
15
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
16
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.
17
Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
18
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.
19
School of Biological Sciences, Nanyang Technological University, Singapore. zbozdech@ntu.edu.sg.

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.

PMID:
25502316
PMCID:
PMC5642863
DOI:
10.1126/science.1260403
[Indexed for MEDLINE]
Free PMC Article

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