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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

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

Copyright © 2015, American Association for the Advancement of Science.

PMID:
25502316
[PubMed - indexed for MEDLINE]
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