1. Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness
- Author
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Sachel Mok, Adama Gansané, Rithea Leang, Clark H. Cunningham, Romaric Nzoumbou-Boko, David A. Fidock, Aline Uwimana, Ioanna Deni, Nina F. Gnädig, Barbara H. Stokes, Marian Warsame, Kelly Rubiano, Leila S. Ross, Olimatou Kolley, Kurt E. Ward, Issa M. Souleymane, Eric Legrand, Frédéric Ariey, Philip J. Rosenthal, Josefine Striepen, Samuel J. Smith, Abdunoor M. Kabanywanyi, Judith Straimer, Jade Bath, Kyra A Schindler, Didier Menard, Mathieu Ndounga, Tim J. Anderson, François Nosten, Claudette Ndayikunda, Tomas Yeo, Satish K. Dhingra, Columbia University Irving Medical Center (CUIMC), Washington University in Saint Louis (WUSTL), Génétique du paludisme et résistance - Malaria Genetics and Resistance, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U1201 (U1201), Unité de Biologie des interactions hôte-parasite (U1201), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Programme National de Lutte Contre le Paludisme au Tchad, Centre National de Recherche et de Formation sur le Paludisme [Ouagadougou, Burkina Faso] (CNRFP), Laboratoire de parasitologie - Laboratory of Parasitology [Bangui], Institut Pasteur de Bangui, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalo-Universitaire de Kamenge [Bujumbura, Burundi] (CHUK), Ifakara Health Institute [Dar-es-Salaam, Tanzania], Rwanda Biomedical Center (RBC), National Malaria Control Programme [Sierra Leone], National Malaria Control Programme [Banjul, Gambia], Programme National de Lutte Contre le Paludisme [Brazzaville, Democratic Republic of the Congo], University of Gothenburg (GU), National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), Mahidol University [Bangkok], Texas Biomedical Research Institute [San Antonio, TX], University of California [San Francisco] (UCSF), University of California, Columbia University Medical Center (CUMC), Columbia University [New York], DAF gratefully acknowledges the US National Institutes of Health (R01 AI109023), the Department of Defense (W81XWH1910086) and the Bill & Melinda Gates Foundation (OPP1201387) for their financial support. BHS was funded in part by T32 AI106711 (PD: D. Fidock). SM is a recipient of a Human Frontiers of Science Program Long-Term Fellowship. CHC was supported in part by the NIH (R01 AI121558, PI: Jonathan Juliano). FN is supported by the Wellcome Trust of Great Britain (Grant ID: 106698). TJCA acknowledges funding support from the NIH (R37 AI048071). DAF and DM gratefully acknowledge the World Health Organization for their funding., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of California [San Francisco] (UC San Francisco), University of California (UC), and Menard, Didier
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0301 basic medicine ,QH301-705.5 ,infectious disease ,Science ,030106 microbiology ,Plasmodium falciparum ,malaria ,global health ,P. falciparum ,Biology ,artemisinin resistance ,medicine.disease_cause ,Southeast asian ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,parasitic diseases ,medicine ,[SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology ,Artemisinin ,Biology (General) ,Genotyping ,CRISPR/Cas9 ,Genetics ,Microbiology and Infectious Disease ,Mutation ,General Immunology and Microbiology ,General Neuroscience ,Point mutation ,microbiology ,General Medicine ,medicine.disease ,biology.organism_classification ,3. Good health ,fitness ,Epidemiology and Global Health ,030104 developmental biology ,Infectious disease (medical specialty) ,[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Medicine ,epidemiology ,ring-stage survival ,[SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology ,Malaria ,Research Article ,medicine.drug - 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.
- Published
- 2022
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