Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 19, 2021
- Source ID
- 10.7554/elife.66277
Entities
People
- Abdunoor M Kabanywanyi
- Adama Gansané
- Aline Uwimana
- Barbara H Stokes
- Clark H Cunningham
- Claudette Ndayikunda
- David A. Fidock
- Didier Ménard
- Eric Legrand
- François Nosten
- Frédéric Ariey
- Ioanna Deni
- Issa M Souleymane
- Jade R Bath
- Josefine Striepen
- Judith Straimer
- Kelly Rubiano
- Kurt E Ward
- Kyra A. Schindler
- Leila S. Ross
- Marian Warsame
- Mathieu Ndounga
- Nina F Gnädig
- Olimatou Kolley
- Philip J Rosenthal
- Rithea Leang
- Romaric Nzoumbou-boko
- Sachel Mok
- Samuel J Smith
- Satish K Dhingra
- Timothy Jc Anderson
- Tomas Yeo
Organizations
- Centre National de Recherche et de Formation sur le Paludisme
- Columbia University
- Gates Foundation
- Institut Pasteur de Bangui
- Mahidol University
- National Institute of Allergy and Infectious Diseases
- National Malaria Center of Cambodia
- National Malaria Control Program
- Paris Descartes University
- Pasteur Institute
- Pollita Institute
- Texas Biomedical Research Institute
- United States Department of Defense
- University Teaching Hospital
- University of California, San Francisco
- University of Gothenburg
- University of North Carolina at Chapel Hill
- University of Otago
- University of Oxford
- Wellcome Trust
- World Health Organization