Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness

  1. Barbara H Stokes
  2. Satish K Dhingra
  3. Kelly Rubiano
  4. Sachel Mok
  5. Judith Straimer
  6. Nina F Gnädig
  7. Ioanna Deni
  8. Kyra A Schindler
  9. Jade R Bath
  10. Kurt E Ward
  11. Josefine Striepen
  12. Tomas Yeo
  13. Leila S Ross
  14. Eric Legrand
  15. Frédéric Ariey
  16. Clark H Cunningham
  17. Issa M Souleymane
  18. Adama Gansané
  19. Romaric Nzoumbou-Boko
  20. Claudette Ndayikunda
  21. Abdunoor M Kabanywanyi
  22. Aline Uwimana
  23. Samuel J Smith
  24. Olimatou Kolley
  25. Mathieu Ndounga
  26. Marian Warsame
  27. Rithea Leang
  28. François Nosten
  29. Timothy Anderson
  30. Philip J Rosenthal
  31. Didier Ménard
  32. David A Fidock  Is a corresponding author
  1. Columbia University Irving Medical Center, United States
  2. Washington University in St. Louis, United States
  3. Institut Pasteur, France
  4. Institut Cochin, France
  5. Programme National de, Chad
  6. Centre National, Burkina Faso
  7. Institute Pasteur of Bangui, Central African Republic
  8. University Teaching Hospital of Kamenge, Burundi
  9. Ifakara Health Institute, Kenya
  10. Rwanda Biomedical Centre, Rwanda
  11. National Malaria Control Programme, Sierra Leone
  12. National Malaria Control Program, Gambia
  13. Programme National de Lutte Contre le Paludisme, Democratic Republic of the Congo
  14. University of Gothenburg, Sweden
  15. National Center for Parasitology, Entomology, and Malaria Control, Cambodia
  16. Mahidol University, Thailand
  17. Texas Biomedical Research Institute, United States
  18. University of California, San Francisco, United States
  19. 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

  1. Barbara H Stokes

    Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Satish K Dhingra

    Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kelly Rubiano

    Molecular Microbiology, Washington University in St. Louis, St. louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4149-4030
  4. Sachel Mok

    Department of Microbiology and Immunology, Columbia University Irving Medical Center, New Yok, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9605-0154
  5. Judith Straimer

    Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nina F Gnädig

    Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ioanna Deni

    Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5266-8243
  8. Kyra A Schindler

    Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jade R Bath

    Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Kurt E Ward

    Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3614-436X
  11. Josefine Striepen

    Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Tomas Yeo

    Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2923-6060
  13. Leila S Ross

    Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Eric Legrand

    Malaria Genetics and Resistance Unit, INSERM U1201, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  15. Frédéric Ariey

    Inserm U1016, Institut Cochin, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  16. Clark H Cunningham

    Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Issa M Souleymane

    Lutte Contre le Paludisme, Programme National de, Ndjamena, Chad
    Competing interests
    The authors declare that no competing interests exist.
  18. Adama Gansané

    de Recherche et de Formation sur le Paludisme, Centre National, Ouagadougou, Burkina Faso
    Competing interests
    The authors declare that no competing interests exist.
  19. Romaric Nzoumbou-Boko

    Laboratory of Parasitology, Institute Pasteur of Bangui, Bangui, Central African Republic
    Competing interests
    The authors declare that no competing interests exist.
  20. Claudette Ndayikunda

    Parasitology, University Teaching Hospital of Kamenge, Bujumbura, Burundi
    Competing interests
    The authors declare that no competing interests exist.
  21. Abdunoor M Kabanywanyi

    Parasitology, Ifakara Health Institute, Dar es Salaam, Kenya
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2980-0429
  22. Aline Uwimana

    Malaria and Other Parasitic Diseases Division, Rwanda Biomedical Centre, Kigali, Rwanda
    Competing interests
    The authors declare that no competing interests exist.
  23. Samuel J Smith

    National Malaria Control Programme, National Malaria Control Programme, Freetown, Sierra Leone
    Competing interests
    The authors declare that no competing interests exist.
  24. Olimatou Kolley

    National Malaria Control Program, National Malaria Control Program, Banjul, Gambia
    Competing interests
    The authors declare that no competing interests exist.
  25. Mathieu Ndounga

    Programme National de Lutte Contre le Paludisme, Programme National de Lutte Contre le Paludisme, Brazzaville, Democratic Republic of the Congo
    Competing interests
    The authors declare that no competing interests exist.
  26. Marian Warsame

    School of Public Health and Community Medicine, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  27. Rithea Leang

    National Center for Parasitology, Entomology, and Malaria Control, National Center for Parasitology, Entomology, and Malaria Control, Phnom Penh, Cambodia
    Competing interests
    The authors declare that no competing interests exist.
  28. François Nosten

    Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7951-0745
  29. Timothy Anderson

    Texas Biomedical Research Institute, San Antonio, United States
    Competing interests
    The authors declare that no competing interests exist.
  30. Philip J Rosenthal

    Department of Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  31. Didier Ménard

    Malaria Genetics and Resistance Unit, INSERM U1201, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  32. David A Fidock

    Microbiology and Immunology, Columbia University Medical Center, New York, United States
    For correspondence
    df2260@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6753-8938

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.

Reviewing Editor

  1. Dominique Soldati-Favre, University of Geneva, Switzerland

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.

Version history

  1. Preprint posted: January 5, 2021 (view preprint)
  2. Received: January 5, 2021
  3. Accepted: July 17, 2021
  4. Accepted Manuscript published: July 19, 2021 (version 1)
  5. Accepted Manuscript updated: July 20, 2021 (version 2)
  6. Version of Record published: July 29, 2021 (version 3)

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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  1. Barbara H Stokes
  2. Satish K Dhingra
  3. Kelly Rubiano
  4. Sachel Mok
  5. Judith Straimer
  6. Nina F Gnädig
  7. Ioanna Deni
  8. Kyra A Schindler
  9. Jade R Bath
  10. Kurt E Ward
  11. Josefine Striepen
  12. Tomas Yeo
  13. Leila S Ross
  14. Eric Legrand
  15. Frédéric Ariey
  16. Clark H Cunningham
  17. Issa M Souleymane
  18. Adama Gansané
  19. Romaric Nzoumbou-Boko
  20. Claudette Ndayikunda
  21. Abdunoor M Kabanywanyi
  22. Aline Uwimana
  23. Samuel J Smith
  24. Olimatou Kolley
  25. Mathieu Ndounga
  26. Marian Warsame
  27. Rithea Leang
  28. François Nosten
  29. Timothy Anderson
  30. Philip J Rosenthal
  31. Didier Ménard
  32. David A Fidock
(2021)
Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness
eLife 10:e66277.
https://doi.org/10.7554/eLife.66277

Share this article

https://doi.org/10.7554/eLife.66277

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