Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum.
Journal
Malaria journal
ISSN: 1475-2875
Titre abrégé: Malar J
Pays: England
ID NLM: 101139802
Informations de publication
Date de publication:
27 Oct 2022
27 Oct 2022
Historique:
received:
26
05
2022
accepted:
18
10
2022
entrez:
28
10
2022
pubmed:
29
10
2022
medline:
1
11
2022
Statut:
epublish
Résumé
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. 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 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
Sections du résumé
BACKGROUND
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
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
RESULTS AND CONCLUSION
CONCLUSIONS
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
Identifiants
pubmed: 36303209
doi: 10.1186/s12936-022-04330-3
pii: 10.1186/s12936-022-04330-3
pmc: PMC9615251
doi:
Substances chimiques
ribosomal protein S10
0
Antimalarials
0
Protozoan Proteins
0
artemisinin
9RMU91N5K2
Artemisinins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
302Subventions
Organisme : Thailand Research Fund
ID : PHD/0234/2558
Organisme : National Center for Genetic Engineering and Biotechnology
ID : RSA5880064
Organisme : National Science and Technology Development Agency
ID : P1450883
Organisme : National Science and Technology Development Agency
ID : P1850116
Organisme : Wellcome Trust
ID : FC001097
Pays : United Kingdom
Organisme : Cancer Research UK
ID : FC001097
Pays : United Kingdom
Organisme : Medical Research Council
ID : FC001097
Pays : United Kingdom
Organisme : Wellcome Trust
ID : FC001097
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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