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

Kampoun, Tanyaluck; Srichairatanakool, Somdet; Prommana, Parichat; Shaw, Philip J.; Green, Judith L.; Knuepfer, Ellen; Holder, Anthony A.; Uthaipibull, Chairat

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 resist-
ant 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 (RSA 0−3 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 RSA 0−3 h. The results suggest epistasis of arps10
and k13, with arps10-V127M a modifier of ART susceptibility in different k13 allele backgrounds.

Citation

Kampoun, T., Srichairatanakool, S., Prommana, P., Shaw, P. J., Green, J. L., Knuepfer, E., Holder, A. A., & Uthaipibull, C. (in press). Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum. Malaria Journal, 21(1), Article 302. https://doi.org/10.1186/s12936-022-04330-3

• Journal Article Type: Article
• Acceptance Date: Oct 18, 2022
• Online Publication Date: Oct 27, 2022
• Deposit Date: Dec 7, 2022
• Publicly Available Date: Dec 13, 2022
• Journal: Malaria Journal
• Electronic ISSN: 1475-2875
• Publisher: BioMed Central
• Peer Reviewed: Peer Reviewed
• Volume: 21
• Issue: 1
• Article Number: 302
• DOI: https://doi.org/10.1186/s12936-022-04330-3
• Keywords: Infectious Diseases; Parasitology
• Additional Information: Received: 26 May 2022; Accepted: 18 October 2022; First Online: 27 October 2022; : ; : The authors declare that they have no competing interests.