Polymorphisms in Plasmodium falciparum Kelch 13 and P. vivax Kelch 12 Genes in Parasites Collected from Three South Pacific Countries Prior to Extensive Exposure to Artemisinin Combination Therapies

Gresty, Karryn; Anderson, Karen; Pasay, Cielo; Waters, Norman C.; Cheng, Qin

doi:10.1128/aac.00536-19

Cited by 6 publications

(5 citation statements)

References 55 publications

(55 reference statements)

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“…Other NGS assays for P. vivax relatedness and population genetic analysis have previously been designed ( Lin et al., 2015 ; Friedrich et al., 2016 ), but none combine these markers with phenotypic markers in a single assay. Variation in drug resistance associated genes has so far primarily been performed with single target assays or WGS ( Auburn et al., 2016 ; Gresty et al., 2019 ; Ferreira et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Novel highly-multiplexed AmpliSeq targeted assay for Plasmodium vivax genetic surveillance use cases at multiple geographical scales

Kattenberg

Nguyen

et al. 2022

Front. Cell. Infect. Microbiol.

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Although the power of genetic surveillance tools has been acknowledged widely, there is an urgent need in malaria endemic countries for feasible and cost-effective tools to implement in national malaria control programs (NMCPs) that can generate evidence to guide malaria control and elimination strategies, especially in the case of Plasmodium vivax. Several genetic surveillance applications (‘use cases’) have been identified to align research, technology development, and public health efforts, requiring different types of molecular markers. Here we present a new highly-multiplexed deep sequencing assay (Pv AmpliSeq). The assay targets the 33-SNP vivaxGEN-geo panel for country-level classification, and a newly designed 42-SNP within-country barcode for analysis of parasite dynamics in Vietnam and 11 putative drug resistance genes in a highly multiplexed NGS protocol with easy workflow, applicable for many different genetic surveillance use cases. The Pv AmpliSeq assay was validated using: 1) isolates from travelers and migrants in Belgium, and 2) routine collections of the national malaria control program at sentinel sites in Vietnam. The assay targets 229 amplicons and achieved a high depth of coverage (mean 595.7 ± 481) and high accuracy (mean error-rate of 0.013 ± 0.007). P. vivax parasites could be characterized from dried blood spots with a minimum of 5 parasites/µL and 10% of minority-clones. The assay achieved good spatial specificity for between-country prediction of origin using the 33-SNP vivaxGEN-geo panel that targets rare alleles specific for certain countries and regions. A high resolution for within-country diversity in Vietnam was achieved using the designed 42-SNP within-country barcode that targets common alleles (median MAF 0.34, range 0.01-0.49. Many variants were detected in (putative) drug resistance genes, with different predominant haplotypes in the pvmdr1 and pvcrt genes in different provinces in Vietnam. The capacity of the assay for high resolution identity-by-descent (IBD) analysis was demonstrated and identified a high rate of shared ancestry within Gia Lai Province in the Central Highlands of Vietnam, as well as between the coastal province of Binh Thuan and Lam Dong. Our approach performed well in geographically differentiating isolates at multiple spatial scales, detecting variants in putative resistance genes, and can be easily adjusted to suit the needs in other settings in a country or region. We prioritize making this tool available to researchers and NMCPs in endemic countries to increase ownership and ensure data usage for decision-making and malaria policy.

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Section: Discussionmentioning

confidence: 99%

Novel highly-multiplexed AmpliSeq targeted assay for Plasmodium vivax genetic surveillance use cases at multiple geographical scales

Kattenberg

Nguyen

et al. 2022

Front. Cell. Infect. Microbiol.

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“…However, several studies have monitored the P. vivax ortholog of pfk13, pvk12 for polymorphisms that might lead to ART resistance [144]. While several polymorphisms have been found in pvkelch12, with low frequencies and limited polymorphisms, such as V552I, K151Q, and M124I (7 of 734, 1%) [146][147][148] Study in Indonesia also found no polymorphism associated with ART resistance [61]. These results suggested a lack of strong selection pressure from ART on pvk12 [144,147].…”

Section: Discussionmentioning

confidence: 99%

Drug resistance of Plasmodium falciparum and Plasmodium vivax isolates in Indonesia

Rahmasari

Asih

Dewayanti

et al. 2022

Malar J

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This review article aims to investigate the genotypic profiles of Plasmodium falciparum and Plasmodium vivax isolates collected across a wide geographic region and their association with resistance to anti-malarial drugs used in Indonesia. A systematic review was conducted between 1991 and date. Search engines, such as PubMed, Science Direct, and Google Scholar, were used for articles published in English and Indonesian to search the literature. Of the 471 initially identified studies, 61 were selected for 4316 P. falciparum and 1950 P. vivax individual infections. The studies included 23 molecular studies and 38 therapeutic efficacy studies. K76T was the most common pfcrt mutation. K76N (2.1%) was associated with the haplotype CVMNN. By following dihydroartemisinin–piperaquine (DHA–PPQ) therapy, the mutant pfmdr1 alleles 86Y and 1034C were selected. Low prevalence of haplotype N86Y/Y184/D1246Ypfmdr1 reduces susceptibility to AS–AQ. SNP mutation pvmdr1 Y976F reached 96.1% in Papua and East Nusa Tenggara. Polymorphism analysis in the pfdhfr gene revealed 94/111 (84.7%) double mutants S108N/C59R or S108T/A16V in Central Java. The predominant pfdhfr haplotypes (based on alleles 16, 51, 59,108, 164) found in Indonesia were ANCNI, ANCSI, ANRNI, and ANRNL. Some isolates carried A437G (35.3%) or A437G/K540E SNPs (26.5%) in pfdhps. Two novel pfdhps mutant alleles, I588F/G and K540T, were associated with six pfdhps haplotypes. The highest prevalence of pvdhfr quadruple mutation (F57L/S58R/T61M/S117T) (61.8%) was detected in Papua. In pvdhps, the only polymorphism before and after 2008 was 383G mutation with 19% prevalence. There were no mutations in the pfk13 gene reported with validated and candidate or associated k13 mutation. An increased copy number of pfpm2, associated with piperaquine resistance, was found only in cases of reinfection. Meanwhile, mutation of pvk12 and pvpm4 I165V is unlikely associated with ART and PPQ drug resistance. DHA–PPQ is still effective in treating uncomplicated falciparum and vivax malaria. Serious consideration should be given to interrupt local malaria transmission and dynamic patterns of resistance to anti-malarial drugs to modify chemotherapeutic policy treatment strategies. The presence of several changes in pfk13 in the parasite population is of concern and highlights the importance of further evaluation of parasitic ART susceptibility in Indonesia. Graphical Abstract

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“…However, several studies have monitored the P. vivax ortholog of pfkelch13 , pvkelch12 , for polymorphisms that may lead to ART resistance ( Brazeau et al, 2016 ; Deng et al, 2016 ; Gresty et al, 2019 ). While several polymorphisms have been found in pvkelch12 , they do not align to the respective mutations in pfkelch1 3 that mediate artemisinin resistance ( Brazeau et al, 2016 ; Deng et al, 2016 ; Gresty et al, 2019 ). These results suggest a lack or reduced selection pressure from ART on pvkelch12 to date.…”

Section: Candidate P Vivax Drug Resistance Genesmentioning

confidence: 99%

“…These results suggest a lack or reduced selection pressure from ART on pvkelch12 to date. Notably there is a lack of persistence of pvkech12 SNPs over time in the GMS, and no polymorphism in pvkelch12 in Papua New Guinea, where one might expect selection pressure from ART indirectly from P. falciparum treatment, or directly as the first-line therapy in this region ( Brazeau et al, 2016 ; Gresty et al, 2019 ). These results suggest a lack of strong selection pressure from ART on pvkelch12 at this time ( Brazeau et al, 2016 ; Gresty et al, 2019 ).…”

Section: Candidate P Vivax Drug Resistance Genesmentioning

confidence: 99%

“…Notably there is a lack of persistence of pvkech12 SNPs over time in the GMS, and no polymorphism in pvkelch12 in Papua New Guinea, where one might expect selection pressure from ART indirectly from P. falciparum treatment, or directly as the first-line therapy in this region ( Brazeau et al, 2016 ; Gresty et al, 2019 ). These results suggest a lack of strong selection pressure from ART on pvkelch12 at this time ( Brazeau et al, 2016 ; Gresty et al, 2019 ). Recently, an alternative gene, pfcoronin , has been identified to confer resistance to ART in P. falciparum but the ortholog has not been studied in P. vivax ( Demas et al, 2018 ).…”

Section: Candidate P Vivax Drug Resistance Genesmentioning

confidence: 99%

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The molecular basis of antimalarial drug resistance in Plasmodium vivax

Buyon

Elsworth

Duraisingh

2021

International Journal for Parasitology: Drugs and Drug Resistan

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Plasmodium vivax is the most geographically widespread cause of human malaria and is responsible for the majority of cases outside of the African continent. While great progress has been made towards eliminating human malaria, drug resistant parasite strains pose a threat towards continued progress. Resistance has arisen to multiple antimalarials in P. vivax, including to chloroquine, which is currently the first line therapy for P. vivax in most regions. Despite its importance, an understanding of the molecular mechanisms of drug resistance in this species remains elusive, in large part due to the complex biology of P. vivax and the lack of in vitro culture. In this review, we will cover the extent and challenges of measuring clinical and in vitro drug resistance in P. vivax. We will consider the roles of candidate drug resistance genes. We will highlight the development of molecular approaches for studying P. vivax biology that provide the opportunity to validate the role of putative drug resistance mutations as well as identify novel mechanisms of drug resistance in this understudied parasite. Validated molecular determinants and markers of drug resistance are essential for the rapid and cost-effective monitoring of drug resistance in P. vivax, and will be useful for optimizing drug regimens and for informing drug policy in control and elimination settings.

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Polymorphisms in Plasmodium falciparum Kelch 13 and P. vivax Kelch 12 Genes in Parasites Collected from Three South Pacific Countries Prior to Extensive Exposure to Artemisinin Combination Therapies

Cited by 6 publications

References 55 publications

Novel highly-multiplexed AmpliSeq targeted assay for Plasmodium vivax genetic surveillance use cases at multiple geographical scales

Novel highly-multiplexed AmpliSeq targeted assay for Plasmodium vivax genetic surveillance use cases at multiple geographical scales

Drug resistance of Plasmodium falciparum and Plasmodium vivax isolates in Indonesia

The molecular basis of antimalarial drug resistance in Plasmodium vivax

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