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Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum
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Document Title
Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum
Author
Kampoun T, Srichairatanakool S, Prommana P, Shaw PJ, Green JL, Knuepfer E, Holder AA, Uthaipibull C
Name from Authors Collection
Scopus Author ID
52364480000
Affiliations
Chiang Mai University; National Science & Technology Development Agency - Thailand; National Center Genetic Engineering & Biotechnology (BIOTEC); Francis Crick Institute; University of London; University of London Royal Veterinary College
Type
Article
Source Title
MALARIA JOURNAL
Year
2022
Volume
21
Issue
1
Open Access
Green Published, gold
Publisher
BMC
DOI
10.1186/s12936-022-04330-3
Format
Abstract
Background: The resistance of Plasmodium falciparum to artemisinin-based (ART) drugs, the front-line drug family used in artemisinin-based combination therapy (ACT) for treatment of malaria, is of great concern. Mutations in the kelch13 (k13) gene (for example, those resulting in the Cys580Tyr [C580Y] variant) were identified as genetic markers for ART-resistant parasites, which suggests they are associated with resistance mechanisms. However, not all resistant parasites contain a k13 mutation, and clearly greater understanding of resistance mechanisms is required. A genome-wide association study (GWAS) found single nucleotide polymorphisms associated with ART-resistance in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2), and crt (chloroquine resistance transporter), in addition to k13 gene mutations, suggesting that these alleles contribute to the resistance phenotype. The importance of the FD and ARPS1 0 variants in ART resistance was then studied since both proteins likely function in the apicoplast, which is a location distinct from that of K13. Methods: The reported mutations were introduced, together with a mutation to produce the k13-C580Y variant into the ART-sensitive 3D7 parasite line and the effect on ART-susceptibility using the 0-3 h ring survival assay (RSA(0-3h)) was investigated. Results and conclusion: Introducing both fd-D193Y and arps10-V127M into a k13-C580Y-containing parasite, but not a wild-type k13 parasite, increased survival of the parasite in the RSA(0-3h). The results suggest epistasis of arps10 and k13, with arps10-V127M a modifier of ART susceptibility in different k13 allele backgrounds.
Funding Sponsor
Programme (NSTDA), Thailand Research Fund [PHD/0234/2558]; Faculty of Medicine research fund, Chiang Mai University, Thailand [05293, 113/2561]; Francis Crick Institute [FC001097]; Cancer Research UK [FC001097]; UK Medical Research Council [FC001097]; Wellcome Trust [FC001097]; National Center for Genetic Engineering and Biotechnology; Thailand Research Fund [RSA5880064]; National Science and Technology Development Agency [P1450883, P1850116]
License
CC BY
Rights
Authors
Publication Source
WOS