Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness
- Columbia University Irving Medical Center, United States
- Washington University in St. Louis, United States
- Institut Pasteur, France
- Institut Cochin, France
- Programme National de, Chad
- Centre National, Burkina Faso
- Institute Pasteur of Bangui, Central African Republic
- University Teaching Hospital of Kamenge, Burundi
- Ifakara Health Institute, Kenya
- Rwanda Biomedical Centre, Rwanda
- National Malaria Control Programme, Sierra Leone
- National Malaria Control Program, Gambia
- Programme National de Lutte Contre le Paludisme, Democratic Republic of the Congo
- University of Gothenburg, Sweden
- National Center for Parasitology, Entomology, and Malaria Control, Cambodia
- Mahidol University, Thailand
- Texas Biomedical Research Institute, United States
- University of California, San Francisco, United States
- Columbia University Medical Center, United States
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1-7.
Article and author information
Author details
Abdunoor M Kabanywanyi
Funding
National Institute of Allergy and Infectious Diseases (R01 AI109023)
- David A Fidock
U.S. Department of Defense (W81XWH1910086)
- David A Fidock
Bill and Melinda Gates Foundation (OPP1201387)
- David A Fidock
Wellcome Trust (106698)
- François Nosten
National Institute of Allergy and Infectious Diseases (R37 AI048071)
- Timothy Anderson
National Institute of Allergy and Infectious Diseases (T32 AI106711)
- David A Fidock
World Health Organization
- Didier Menard
World Health Organization
- David A Fidock
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Health care facilities were in charge of collecting anonymized P. falciparum positive cases. Identification of individuals cannot be established. The studies were approved by ethics committees listed in Supplementary file 1. We note that the sponsors had no role in the study design or in the collection or analysis of the data. There was no confidentiality agreement between the sponsors and the investigators.
Copyright
© 2021, Stokes et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness
eLife 10:e66277.
https://doi.org/10.7554/eLife.66277
Further reading
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- Epidemiology and Global Health
Background:
The role of circulating metabolites on child development is understudied. We investigated associations between children’s serum metabolome and early childhood development (ECD).
Methods:
Untargeted metabolomics was performed on serum samples of 5004 children aged 6–59 months, a subset of participants from the Brazilian National Survey on Child Nutrition (ENANI-2019). ECD was assessed using the Survey of Well-being of Young Children’s milestones questionnaire. The graded response model was used to estimate developmental age. Developmental quotient (DQ) was calculated as the developmental age divided by chronological age. Partial least square regression selected metabolites with a variable importance projection ≥1. The interaction between significant metabolites and the child’s age was tested.
Results:
Twenty-eight top-ranked metabolites were included in linear regression models adjusted for the child’s nutritional status, diet quality, and infant age. Cresol sulfate (β=–0.07; adjusted-p <0.001), hippuric acid (β=–0.06; adjusted-p <0.001), phenylacetylglutamine (β=–0.06; adjusted-p <0.001), and trimethylamine-N-oxide (β=–0.05; adjusted-p=0.002) showed inverse associations with DQ. We observed opposite directions in the association of DQ for creatinine (for children aged –1 SD: β=–0.05; pP=0.01;+1 SD: β=0.05; p=0.02) and methylhistidine (–1 SD: β = - 0.04; p=0.04;+1 SD: β=0.04; p=0.03).
Conclusions:
Serum biomarkers, including dietary and microbial-derived metabolites involved in the gut-brain axis, may potentially be used to track children at risk for developmental delays.
Funding:
Supported by the Brazilian Ministry of Health and the Brazilian National Research Council.
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- Epidemiology and Global Health
- Microbiology and Infectious Disease
Several areas of the world suffer a notably high incidence of Shiga toxin-producing Escherichia coli. To assess the impact of persistent cross-species transmission systems on the epidemiology of E. coli O157:H7 in Alberta, Canada, we sequenced and assembled E. coli O157:H7 isolates originating from collocated cattle and human populations, 2007–2015. We constructed a timed phylogeny using BEAST2 using a structured coalescent model. We then extended the tree with human isolates through 2019 to assess the long-term disease impact of locally persistent lineages. During 2007–2015, we estimated that 88.5% of human lineages arose from cattle lineages. We identified 11 persistent lineages local to Alberta, which were associated with 38.0% (95% CI 29.3%, 47.3%) of human isolates. During the later period, six locally persistent lineages continued to be associated with human illness, including 74.7% (95% CI 68.3%, 80.3%) of reported cases in 2018 and 2019. Our study identified multiple locally evolving lineages transmitted between cattle and humans persistently associated with E. coli O157:H7 illnesses for up to 13 y. Locally persistent lineages may be a principal cause of the high incidence of E. coli O157:H7 in locations such as Alberta and provide opportunities for focused control efforts.
