Association of a Novel Mutation in the Plasmodium falciparum Chloroquine Resistance Transporter With Decreased Piperaquine Sensitivity

Agrawal, Sonia; Moser, Kara A; Morton, Lindsay; Cummings, Michael P.; Parihar, Ankita; Dwivedi, Ankit; Shetty, Amol C.; Drábek, Elliott F.; Jacob, Christopher G; Henrich, Philipp P.; Parobek, Christian M.; Jongsakul, Krisada; Huy, Rekol; Spring, Michele; Lanteri, Charlotte; Chaorattanakawee, Suwanna; Lon, Chanthap; Fukuda, Mark M.; Saunders, David; Fidock, David A.; Lin, Jessica T.; Juliano, Jonathan J.; Plowe, Christopher V.; Silva, Joana C.; Takala-Harrison, Shannon

doi:10.1093/infdis/jix334

Cited by 113 publications

(120 citation statements)

References 35 publications

Supporting

Mentioning

114

Contrasting

Order By: Relevance

“…Mutations were found in the chloroquine resistance transporter (PfCRT) agreeing with reported mutations found in some parasites following ACT treatment( 18 ). None of the isolates, however, carried mutations in PfCRT loci recently associated with increased DHA-piperaquine treatment failure ( 6, 7, 19 ).…”

Section: Resultsmentioning

confidence: 96%

Artemisinin-resistant malaria parasites show enhanced transmission to mosquitoes under drug pressure

Witmer

Dahalan

Delves

et al. 2020

Preprint

View full text Add to dashboard Cite

25 Resistance to artemisinin combination therapy (ACT) in the Plasmodium falciparum 26 parasite is threatening to reverse recent gains in reducing global deaths from malaria. 27 Whilst resistance manifests as delayed asexual parasite clearance in patients following 28 ACT treatment, the phenotype can only spread geographically via the sexual cycle and 29 subsequent transmission through the mosquito. Artemisinin and its derivatives (such as 30 dihydroartemisinin, DHA) as well as killing the asexual parasite form are known to sterilize 31 male, sexual-stage gametes from activation. Whether resistant parasites overcome this 32 artemisinin-dependent sterilizing effect has not, however, been fully tested. Here, we 33 analysed five P. falciparum clinical isolates from the Greater Mekong Subregion, each of 34 which demonstrated delayed clinical clearance and carried known resistance-associated 35 polymorphisms in the Kelch13 gene (PfK13 var ). As well as demonstrating reduced 36 sensitivity to artemisinin-derivates in in vitro asexual growth assays, certain PfK13 var 37isolates also demonstrated a marked reduction in sensitivity to these drugs in an in vitro 38 male gamete activation assay compared to a sensitive control. Importantly, the same 39 reduction in sensitivity to DHA was observed when the most resistant isolate was assayed 40 by standard membrane feeding assays using Anopheles stephensi mosquitoes. These 41 results indicate that ACT use can favour resistant over sensitive parasite transmission. A 42 selective advantage for resistant parasite transmission could also favour acquisition of 43 further polymorphisms, such as mosquito host-specificity or antimalarial partner-drug 44 resistance in mixed infections. Favoured transmission of resistance under ACT coverage 45 could have profound implications for the spread of multidrug resistant malaria beyond 46 Southeast Asia. 47

show abstract

Section: Resultsmentioning

confidence: 96%

Artemisinin-resistant malaria parasites show enhanced transmission to mosquitoes under drug pressure

Witmer

Dahalan

Delves

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The crt locus is also relevant to other types of drug resistance, e.g. crt variants that are relatively specific to SE Asia form the genetic background of artemisinin resistance, and newly emerging crt alleles have been associated with the spread of ACT failure due to piperaquine resistance 13,14,22,68 .…”

Section: Chloroquine Resistancementioning

confidence: 99%

An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples

Pearson

Amato

Kwiatkowski

2019

Preprint

View full text Add to dashboard Cite

MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination. MethodsAll samples in this study were derived from blood samples obtained from patients with P. falciparum malaria, collected with informed consent from the patient or a parent or guardian. At each location, sample collection was approved by the appropriate local and institutional ethics committees. The following local and institutional committees gave ethical approval for the partner studies:Standard laboratory protocols were used to determine DNA quantity and proportion of human DNA in each sample as previously described 7,56 .

show abstract

“…The ongoing analysis relating the markers of resistance to clinical outcome may provide some insights regarding this question. It is still debated whether additional genetic modifications in the P. falciparum chloroquine resistance transporter gene are required to confer such resistance (43, 44). Indeed, recent genomic and biological investigations have revealed a rapid increase in the prevalence of novel Pfcrt mutations in Cambodia (H97Y, F145I, M343L, and G353V).…”

Section: Discussionmentioning

confidence: 99%

High proportion of multiple copies of Plasmodium falciparum Plasmepsin-2 gene in African isolates: Is piperaquine resistance emerging in Africa?

Leroy

Macintyre

Adamy

et al. 2018

Preprint

View full text Add to dashboard Cite

28Emergence of Plasmodium falciparum resistance to antimalarial drugs is currently the primary rationale 29 supporting the development of new and well-tolerated drugs. In 2014-2015, a phase 2b clinical study 30 was conducted to evaluate the efficacy of a single oral dose of Artefenomel (OZ439)-piperaquine (PPQ) 31 in Asian and African patients presenting with uncomplicated falciparum malaria. Blood samples 32 collected before treatment offered the opportunity to investigate the proportion of multidrug resistant 33 parasite genotypes including P. falciparum Kelch13 mutations and copy number variation of both P. 34 falciparum plasmepsin2 (Pfpm2) and P. falciparum multidrug resistance 1 (Pfmdr1) genes. 35Validated Kelch13 resistance mutations including C580Y, I543T, P553L and V568G were only 36 detected in parasites from Vietnamese patients. In Africa, isolates with multiple copies of the Pfmdr1 37 gene were shown to be more frequent than previously reported (21.1%, range from 12.4% in Burkina 38Faso to 27.4% in Uganda). More strikingly, high proportions of isolates with multiple copies of the 39 Pfpm2 gene, associated to PPQ resistance, were frequently observed in the African sites, especially in 40 Burkina Faso and Uganda (>30%). 41 Our findings sharply contrast with the recent description of increased sensitivity to PPQ of Ugandan 42 parasite isolates. This emphasizes the necessity to decipher the genetic background associated with PPQ 43 resistance in Africa by investigating in vitro susceptibilities to PPQ of isolates with multiple copies of 44 the Pfpm2 gene and the urgent need to assess the risk of development of PPQ resistance, along with the 45 efficacy of both current frontline therapies and new antimalarial combinations. 46 47 48 49 50 51 52 Michael Ramharter) and MMV staff involved in study conduct, data collection and reporting (Helen 311 Demarest, Stephan Duparc, Sophie Biguenet). MMV would also like to acknowledge their development 312 partner Sanofi-Aventis.

show abstract

Association of a Novel Mutation in the Plasmodium falciparum Chloroquine Resistance Transporter With Decreased Piperaquine Sensitivity

Abstract: Our data suggest that, in addition to plasmepsin II/III copy number, other loci, including pfcrt, may also be involved in piperaquine resistance.

Cited by 113 publications

References 35 publications

Artemisinin-resistant malaria parasites show enhanced transmission to mosquitoes under drug pressure

Artemisinin-resistant malaria parasites show enhanced transmission to mosquitoes under drug pressure

An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples

High proportion of multiple copies of Plasmodium falciparum Plasmepsin-2 gene in African isolates: Is piperaquine resistance emerging in Africa?

Contact Info

Product

Resources

About