Local emergence in Amazonia of Plasmodium falciparum k13 C580Y mutants associated with in vitro artemisinin resistance

eLife

Yassamine Lazrek¹  Horace Cox²  David A Fidock³  Sachel Mok⁴  Quacy Grant⁵  Jeanne-Celeste Paquet⁶  Naomi W Lucchi⁶  Lise Musset⁷  Maria-Paz Ade⁸  Luana C Mathieu⁸  Venkatachalam Udhayakumar⁹  Magalie Demar⁹  Angela M Early^1,10  Jean SF Alexandre^1,10  Pascal Ringwald^1,11  Daniel E Neafsey^1,12 

[1] Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, United States;Ecole Doctorale n°587, Diversités, Santé, et Développement en Amazonie, Université de Guyane, Cayenne, French Guiana;Ecosystèmes Amazoniens et Pathologie Tropicale (EPAT), EA3593, Université de Guyane, Cayenne, French Guiana;Broad Institute of MIT and Harvard, Cambridge, United States;Department of Communicable Diseases and Environmental Determinants of Health, Pan American Health Organization/World Health Organization, Washington, United States;Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, United States;Global Malaria Program, World Health Organization, Geneva, Switzerland;Laboratoire de parasitologie, Centre Nationale de Référence du Paludisme, World Health Organization Collaborating Center for surveillance of antimalarial drug resistance, Institut Pasteur de la Guyane, Cayenne, French Guiana;Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, United States;Ministry of Public Health, Georgetown, Guyana;Pan American Health Organization, Georgetown, Guyana;Service de Maladies Infectieuses et Tropicales, Centre Hospitalier Andrée Rosemon, Cayenne, French Guiana;

关键词: Guyana;    artemisinin resistance;    evolution;    kelch 13;    South America;    malaria;   

DOI  :  10.7554/eLife.51015

来源: DOAJ

【 摘 要 】

Antimalarial drug resistance has historically arisen through convergent de novo mutations in Plasmodium falciparum parasite populations in Southeast Asia and South America. For the past decade in Southeast Asia, artemisinins, the core component of first-line antimalarial therapies, have experienced delayed parasite clearance associated with several pfk13 mutations, primarily C580Y. We report that mutant pfk13 has emerged independently in Guyana, with genome analysis indicating an evolutionary origin distinct from Southeast Asia. Pfk13 C580Y parasites were observed in 1.6% (14/854) of samples collected in Guyana in 2016–2017. Introducing pfk13 C580Y or R539T mutations by gene editing into local parasites conferred high levels of in vitro artemisinin resistance. In vitro growth competition assays revealed a fitness cost associated with these pfk13 variants, potentially explaining why these resistance alleles have not increased in frequency more quickly in South America. These data place local malaria control efforts at risk in the Guiana Shield.

【 授权许可】

Unknown