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Population genomics and transcriptomics of Plasmodium falciparum in Cambodia and Vietnam uncover key components of the artemisinin resistance genetic background

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Nayak, Sourav, Peto, Thomas J., Kucharski, Michal, Tripura, Rupam, Callery, James J., Quang Huy, Duong Tien, Gendrot, Mathieu, Lek, Dysoley, Nghia, Ho Dang Trung, van der Pluijm, Rob W., Dong, Nguyen, Long, Le Thanh, Vongpromek, Ranitha, Rekol, Huy, Hoang Chau, Nguyen, Miotto, Olivo, Mukaka, Mavuto, Dhorda, Mehul, von Seidlein, Lorenz, Imwong, Mallika, Roca, Xavier, Day, Nicholas P. J., White, Nicholas J., Dondorp, Arjen M., Bozdech, Zbynek·2024·Nature Communications
DOI 10.1038/s41467-024-54915-6PMC PMC11621345

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Abstract

Abstract The emergence and spread of Plasmodium falciparum lineages resistant to artemisinins is threatening the efficacy of Artemisinin Combination Therapies (ACTs), the global first-line treatment for falciparum malaria. Artemisinin resistance is a complex genetic trait in which nonsynonymous SNPs in PfK13 cooperate with other, currently unknown, genetic variations to mediate the resistance phenotype. To identify these new molecular factors, we carried out population genomic/transcriptomic analyses of P. falciparum collected from patients with uncomplicated malaria in Cambodia and Vietnam between 2018 and 2020. GWAS confirmed the strong association of mutations in PfK13, in particular C580Y, with artemisinin resistance, but also uncovered significant associations with several additional polymorphisms, including PfRad5 in which two nonsynonymous mutations (N1131I and N821K) were independently associated with artemisinin resistance since its emergence. In addition, an intronic SNP in the gene encoding a WD40 repeat-containing protein on chromosome 11 (PfWD11) was associated. Population transcriptome analyses revealed a defined set of genes whose steady-state levels of mRNA and/or alternatively spliced or antisense transcripts correlated with artemisinin resistance. Using transcriptomics of sequential parasite samples after the start of ACT treatment, we also characterized in vivo transcriptional responses to artemisinins and demonstrated the capacity of the resistant parasites to decelerate their intraerythrocytic developmental cycle, which can contribute to the resistant phenotype. During this process, both PfRAD5 and PfWD11 appear to upregulate an alternatively spliced isoform suggesting a contribution to the protective response to artemisinins. Comparison with historical samples indicated that PfRad5 and PfWD11 have been under selective pressure since the emergence of artemisinin resistance in the Greater Mekong Subregion as covariates of PfK13. Hence both genes now represent new high-confidence markers presumably as the key elements of the artemisinin resistance genetic background.

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Metadata

Authors
Nayak, S., Peto, T. J., Kucharski, M., Tripura, R., Callery, J. J., Quang Huy, D. T., Gendrot, M., Lek, D., Nghia, H. D. T., van der Pluijm, R. W., Dong, N., Long, L. T., Vongpromek, R., Rekol, H., Hoang Chau, N., Miotto, O., Mukaka, M., Dhorda, M., von Seidlein, L., Imwong, M., Roca, X., Day, N. P. J., White, N. J., Dondorp, A. M., & Bozdech, Z.
Affiliations
  • Nanyang Technological University (SG)
  • Mahidol University (TH)
  • Cambodia National Malaria Center (KH)
  • Pham Ngoc Thach University of Medicine (VN)
  • Institut Pasteur (FR)
  • Khanh Hoa General Hospital (VN)
Corresponding author
  • Dondorp, Arjen M.
  • Bozdech, Zbynek
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-12-05
Volume
15
Issue
1
Pages
10625-10625
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-54915-6
PMC
PMC11621345
OpenAlex
W4405056416
Cited by
15
References
1
Citations by year
2026: 6 · 2025: 6 · 2024: 3
FWCI
6.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DR-NTU (Nanyang Technological University) (publishedVersion, cc-by-nc-nd)
  • Pure Amsterdam UMC (publishedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Ministry of Education - Singapore (#MOE2019-T3-1-007)
  • Ministry of Education, India
  • Medical Research Council
  • National Medical Research Council
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Phytochemical compounds biological activities
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
Plasmodium falciparum, artemisinin resistance, pfk13, non-synonymous SNPs, alternative splicing, antisense transcripts, intraerythrocytic developmental cycle, selection pressure, Greater Mekong Subregion, uncomplicated malaria, Cambodia, Vietnam
MeSH terms
Antimalarials, Cambodia, Drug Resistance, Humans, Plasmodium falciparum, Vietnam, Protozoan Proteins, Malaria, Falciparum, Polymorphism, Single Nucleotide, Gene Expression Profiling, Genomics, Artemisinins, Transcriptome

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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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