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

eLife

Adama Gansané¹  Clark H Cunningham²  Philip J Rosenthal³  Leila S Ross⁴  Tomas Yeo⁴  Kelly Rubiano⁴  Satish K Dhingra⁴  Nina F Gnädig⁴  Sachel Mok⁴  Jade R Bath⁴  Josefine Striepen⁴  Kyra A Schindler⁴  Ioanna Deni⁴  Barbara H Stokes⁴  Judith Straimer⁴  Kurt E Ward⁵  David A Fidock⁶  Abdunoor M Kabanywanyi⁷  Frédéric Ariey⁸  Romaric Nzoumbou-Boko⁹  Eric Legrand^1,10  Didier Ménard^1,10  Aline Uwimana^1,11  Rithea Leang^1,12  Olimatou Kolley^1,13  Samuel J Smith^1,14  Issa M Souleymane^1,15  Mathieu Ndounga^1,16  Marian Warsame^1,17  François Nosten^1,18  Timothy JC Anderson^1,19  Claudette Ndayikunda^2,20 

[1] Centre National de Recherche et de Formation sur le Paludisme, Ouagadougou, Burkina Faso;Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States;Department of Medicine, University of California, San Francisco, San Francisco, United States;Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States;Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States;Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand;Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, United States;Ifakara Health Institute, Dar es Salaam, United Republic of Tanzania;Institut Cochin, INSERM U1016, Université Paris Descartes, Paris, France;Laboratoire de Parasitologie, Institut Pasteur de Bangui, Bangui, Central African Republic;Malaria Genetics and Resistance Unit, Institut Pasteur, INSERM U1201, CNRS ERL9195, Paris, France;Malaria and Other Parasitic Diseases Division, Rwanda Biomedical Centre, Kigali, Rwanda;National Center for Parasitology, Entomology & Malaria Control, Phnom Penh, Cambodia;National Malaria Control Program, Banjul, Gambia;National Malaria Control Program, Freetown, Sierra Leone;Programme National de Lutte Contre le Paludisme au Tchad, Ndjamena, Chad;Programme National de Lutte Contre le Paludisme, Brazzaville, Democratic Republic of the Congo;School of Public Health and Community Medicine, University of Gothenburg, Gothenburg, Sweden;Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand;Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom;Texas Biomedical Research Institute, San Antonio, United States;University Teaching Hospital of Kamenge, Bujumbura, Burundi;

关键词: Plasmodium falciparum;    malaria;    artemisinin resistance;    CRISPR/Cas9;    ring-stage survival;    fitness;    P. falciparum;   

DOI  :  10.7554/eLife.66277

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY