Author:
Kampoun Tanyaluck,Srichairatanakool Somdet,Prommana Parichat,Shaw Philip J.,Green Judith L.,Knuepfer Ellen,Holder Anthony A.,Uthaipibull Chairat
Abstract
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 ARPS10 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 (RSA0−3 h) 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 RSA0−3 h. The results suggest epistasis of arps10 and k13, with arps10-V127M a modifier of ART susceptibility in different k13 allele backgrounds.
Funder
Thailand Research Fund
National Center for Genetic Engineering and Biotechnology
National Science and Technology Development Agency
Francis Crick Institute
Cancer Research UK
Medical Research Council
Wellcome Trust
Publisher
Springer Science and Business Media LLC
Subject
Infectious Diseases,Parasitology
Cited by
5 articles.
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