Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum
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 Cys580T...
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ftdoajarticles:oai:doaj.org/article:3196b35f1366420a955e8f0b0687d746 2023-05-15T15:12:28+02:00 Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum Tanyaluck Kampoun Somdet Srichairatanakool Parichat Prommana Philip J. Shaw Judith L. Green Ellen Knuepfer Anthony A. Holder Chairat Uthaipibull 2022-10-01T00:00:00Z https://doi.org/10.1186/s12936-022-04330-3 https://doaj.org/article/3196b35f1366420a955e8f0b0687d746 EN eng BMC https://doi.org/10.1186/s12936-022-04330-3 https://doaj.org/toc/1475-2875 doi:10.1186/s12936-022-04330-3 1475-2875 https://doaj.org/article/3196b35f1366420a955e8f0b0687d746 Malaria Journal, Vol 21, Iss 1, Pp 1-10 (2022) Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 article 2022 ftdoajarticles https://doi.org/10.1186/s12936-022-04330-3 2022-12-30T23:05:22Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Malaria Journal 21 1 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
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Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
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Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 Tanyaluck Kampoun Somdet Srichairatanakool Parichat Prommana Philip J. Shaw Judith L. Green Ellen Knuepfer Anthony A. Holder Chairat Uthaipibull Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
description |
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. |
format |
Article in Journal/Newspaper |
author |
Tanyaluck Kampoun Somdet Srichairatanakool Parichat Prommana Philip J. Shaw Judith L. Green Ellen Knuepfer Anthony A. Holder Chairat Uthaipibull |
author_facet |
Tanyaluck Kampoun Somdet Srichairatanakool Parichat Prommana Philip J. Shaw Judith L. Green Ellen Knuepfer Anthony A. Holder Chairat Uthaipibull |
author_sort |
Tanyaluck Kampoun |
title |
Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum |
title_short |
Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum |
title_full |
Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum |
title_fullStr |
Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum |
title_full_unstemmed |
Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum |
title_sort |
apicoplast ribosomal protein s10-v127m enhances artemisinin resistance of a kelch13 transgenic plasmodium falciparum |
publisher |
BMC |
publishDate |
2022 |
url |
https://doi.org/10.1186/s12936-022-04330-3 https://doaj.org/article/3196b35f1366420a955e8f0b0687d746 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Malaria Journal, Vol 21, Iss 1, Pp 1-10 (2022) |
op_relation |
https://doi.org/10.1186/s12936-022-04330-3 https://doaj.org/toc/1475-2875 doi:10.1186/s12936-022-04330-3 1475-2875 https://doaj.org/article/3196b35f1366420a955e8f0b0687d746 |
op_doi |
https://doi.org/10.1186/s12936-022-04330-3 |
container_title |
Malaria Journal |
container_volume |
21 |
container_issue |
1 |
_version_ |
1766343135277875200 |