Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness
- Columbia University Irving Medical Center, United States
- Washington University in St. Louis, United States
- Institut Pasteur, France
- Institut Cochin, France
- Programme National de, Chad
- Centre National, Burkina Faso
- Institute Pasteur of Bangui, Central African Republic
- University Teaching Hospital of Kamenge, Burundi
- Ifakara Health Institute, Kenya
- Rwanda Biomedical Centre, Rwanda
- National Malaria Control Programme, Sierra Leone
- National Malaria Control Program, Gambia
- Programme National de Lutte Contre le Paludisme, Democratic Republic of the Congo
- University of Gothenburg, Sweden
- National Center for Parasitology, Entomology, and Malaria Control, Cambodia
- Mahidol University, Thailand
- Texas Biomedical Research Institute, United States
- University of California, San Francisco, United States
- Columbia University Medical Center, United States
Abstract
The emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failure across Southeast Asia. In Africa, K13-propeller genotyping confirms the emergence of the R561H mutation in Rwanda and highlights the continuing dominance of wild-type K13 elsewhere. Using gene editing, we show that R561H, along with C580Y and M579I, confer elevated in vitro ART resistance in some African strains, contrasting with minimal changes in ART susceptibility in others. C580Y and M579I cause substantial fitness costs, which may slow their dissemination in high-transmission settings, in contrast with R561H that in African 3D7 parasites is fitness neutral. In Cambodia, K13 genotyping highlights the increasing spatio-temporal dominance of C580Y. Editing multiple K13 mutations into a panel of Southeast Asian strains reveals that only the R561H variant yields ART resistance comparable to C580Y. In Asian Dd2 parasites C580Y shows no fitness cost, in contrast with most other K13 mutations tested, including R561H. Editing point mutations in ferredoxin or mdr2, earlier associated with resistance, has no impact on ART susceptibility or parasite fitness. These data underline the complex interplay between K13 mutations, parasite survival, growth and genetic background in contributing to the spread of ART resistance.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1-7.
Article and author information
Author details
Abdunoor M Kabanywanyi
Funding
National Institute of Allergy and Infectious Diseases (R01 AI109023)
- David A Fidock
U.S. Department of Defense (W81XWH1910086)
- David A Fidock
Bill and Melinda Gates Foundation (OPP1201387)
- David A Fidock
Wellcome Trust (106698)
- François Nosten
National Institute of Allergy and Infectious Diseases (R37 AI048071)
- Timothy Anderson
National Institute of Allergy and Infectious Diseases (T32 AI106711)
- David A Fidock
World Health Organization
- Didier Menard
World Health Organization
- David A Fidock
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Health care facilities were in charge of collecting anonymized P. falciparum positive cases. Identification of individuals cannot be established. The studies were approved by ethics committees listed in Supplementary file 1. We note that the sponsors had no role in the study design or in the collection or analysis of the data. There was no confidentiality agreement between the sponsors and the investigators.
Copyright
© 2021, Stokes et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness
eLife 10:e66277.
https://doi.org/10.7554/eLife.66277
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