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

Barbara H. Stokes 1 Satish K. Dhingra 1 Kelly Rubiano 2 Sachel Mok 1 Judith Straimer 1 Nina F. Gnadig 1 Ioanna Deni 1 Kyra A. Schindler 1 Jade R. Bath 1 Kurt E. Ward 1 Josefine Striepen 1 Tomas Yeo 1 Leila S. Ross 1 Eric Legrand 3, 4 Frédéric Ariey 5 Clark H. Cunningham 1 Issa M. Souleymane 6 Adama Gansané 7 Romaric Nzoumbou-Boko 8 Claudette Ndayikunda 9 Abdunoor M. Kabanywanyi 10 Aline Uwimana 11 Samuel J. Smith 12 Olimatou Kolley 13 Mathieu Ndounga 14 Marian Warsame 15 Rithea Leang 16 François Nosten 17 Timothy Anderson 18 Phillip J. Rosenthal 19 Didier Menard 3, 4 David A. Fidock 20, * 
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.
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Submitted on : Monday, July 19, 2021 - 6:51:17 PM
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Barbara H. Stokes, Satish K. Dhingra, Kelly Rubiano, Sachel Mok, Judith Straimer, et al.. Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness. eLife, eLife Sciences Publication, 2021, 10, pp.e66277. ⟨10.7554/eLife.66277⟩. ⟨pasteur-03291682⟩



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