Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum

被引:4
|
作者
Kampoun, Tanyaluck [1 ]
Srichairatanakool, Somdet [1 ]
Prommana, Parichat [2 ]
Shaw, Philip J. [2 ]
Green, Judith L. [3 ]
Knuepfer, Ellen [3 ,4 ]
Holder, Anthony A. [3 ]
Uthaipibull, Chairat [2 ,5 ]
机构
[1] Chiang Mai Univ, Fac Med, Dept Biochem, Chiang Mai 50200, Thailand
[2] Natl Ctr Genet Engn & Biotechnol BIOTEC, Med Mol Biotechnol Res Grp, 113 Thailand Sci Pk,Phahonyothin Rd, Khlong Luang 12120, Pathum Thani, Thailand
[3] Francis Crick Inst, Malaria Parasitol Lab, 1 Midland Rd, London NW1 1AT, England
[4] Royal Vet Coll, Dept Pathobiol & Populat Sci, Mol & Cellular Parasitol Lab, Hawkshead Lane, Hatfield AL9 7TA, Herts, England
[5] Thailand Ctr Excellence Life Sci TCELS, Bangkok 10400, Thailand
基金
英国医学研究理事会; 英国惠康基金;
关键词
MALARIA;
D O I
10.1186/s12936-022-04330-3
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
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.
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页数:10
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