Publication: Plasmodium falciparum k13 mutations in africa and asia impact artemisinin resistance and parasite fitness
Issued Date
2021-07-01
Resource Type
ISSN
2050084X
Other identifier(s)
2-s2.0-85111596239
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Mahidol University
Rights Holder(s)
SCOPUS
Bibliographic Citation
eLife. Vol.10, (2021)
Suggested Citation
Barbara H. Stokes, Satish K. Dhingra, Kelly Rubiano, Sachel Mok, Judith Straimer, Nina F. Gnädig, Ioanna Deni, Kyra A. Schindler, Jade R. Bath, Kurt E. Ward, Josefine Striepen, Tomas Yeo, Leila S. Ross, Eric Legrand, Frédéric Ariey, Clark H. Cunningham, Issa M. Souleymane, Adama Gansané, Romaric Nzoumbou-Boko, Claudette Ndayikunda, Abdunoor M. Kabanywanyi, Aline Uwimana, Samuel J. Smith, Olimatou Kolley, Mathieu Ndounga, Marian Warsame, Rithea Leang, François Nosten, Timothy J.C. Anderson, Philip J. Rosenthal, Didier Ménard, David A. Fidock Plasmodium falciparum k13 mutations in africa and asia impact artemisinin resistance and parasite fitness. eLife. Vol.10, (2021). doi:10.7554/eLife.66277 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/76112
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Title
Plasmodium falciparum k13 mutations in africa and asia impact artemisinin resistance and parasite fitness
Author(s)
Barbara H. Stokes
Satish K. Dhingra
Kelly Rubiano
Sachel Mok
Judith Straimer
Nina F. Gnädig
Ioanna Deni
Kyra A. Schindler
Jade R. Bath
Kurt E. Ward
Josefine Striepen
Tomas Yeo
Leila S. Ross
Eric Legrand
Frédéric Ariey
Clark H. Cunningham
Issa M. Souleymane
Adama Gansané
Romaric Nzoumbou-Boko
Claudette Ndayikunda
Abdunoor M. Kabanywanyi
Aline Uwimana
Samuel J. Smith
Olimatou Kolley
Mathieu Ndounga
Marian Warsame
Rithea Leang
François Nosten
Timothy J.C. Anderson
Philip J. Rosenthal
Didier Ménard
David A. Fidock
Satish K. Dhingra
Kelly Rubiano
Sachel Mok
Judith Straimer
Nina F. Gnädig
Ioanna Deni
Kyra A. Schindler
Jade R. Bath
Kurt E. Ward
Josefine Striepen
Tomas Yeo
Leila S. Ross
Eric Legrand
Frédéric Ariey
Clark H. Cunningham
Issa M. Souleymane
Adama Gansané
Romaric Nzoumbou-Boko
Claudette Ndayikunda
Abdunoor M. Kabanywanyi
Aline Uwimana
Samuel J. Smith
Olimatou Kolley
Mathieu Ndounga
Marian Warsame
Rithea Leang
François Nosten
Timothy J.C. Anderson
Philip J. Rosenthal
Didier Ménard
David A. Fidock
Other Contributor(s)
Faculty of Tropical Medicine, Mahidol University
Rwanda Biomedical Center
Institut Pasteur de Bangui
Ifakara Health Institute
Institut Cochin
Columbia University Irving Medical Center
The University of North Carolina at Chapel Hill
Texas Biomedical Research Institute
University of California, San Francisco
University of Otago
Göteborgs Universitet
Nuffield Department of Medicine
CNRS Centre National de la Recherche Scientifique
National AIDS Control Programme
Programme National de Lutte Contre le Paludisme au Tchad
University Teaching Hospital of Kamenge
Programme National de Lutte Contre le Paludisme
National Center for Parasitology
National Malaria Control Programme
Centre National de Recherche et de Formation sur le Paludisme
Rwanda Biomedical Center
Institut Pasteur de Bangui
Ifakara Health Institute
Institut Cochin
Columbia University Irving Medical Center
The University of North Carolina at Chapel Hill
Texas Biomedical Research Institute
University of California, San Francisco
University of Otago
Göteborgs Universitet
Nuffield Department of Medicine
CNRS Centre National de la Recherche Scientifique
National AIDS Control Programme
Programme National de Lutte Contre le Paludisme au Tchad
University Teaching Hospital of Kamenge
Programme National de Lutte Contre le Paludisme
National Center for Parasitology
National Malaria Control Programme
Centre National de Recherche et de Formation sur le Paludisme
Abstract
The emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failures 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 of 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.
