Plasmepsin II–III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum

Bopp, Selina; Magistrado, Pamela; Wong, Waichi; Schaffner, Stephen F.; Mukherjee, Avinaba; Lim, Pharath; Dhorda, Mehul; Amaratunga, Chanaki; Woodrow, Charles J.; Ashley, Elizabeth A.; White, Nicholas J.; Dondorp, Arjen M.; Fairhurst, Rick M.; Ariey, Frédéric; Ménard, Didier; Wirth, Dyann F.; Volkman, Sarah K.

doi:10.1038/s41467-018-04104-z

Cited by 93 publications

(140 citation statements)

References 49 publications

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“…The lack of a consistent pattern of reduced sensitivity to artemisinin-based drugs across PfK13 var isolates suggests that K13 polymorphisms alone likely do not completely explain sensitivity of sexual stages to artemisinin treatment. This observation is corroborated by similar findings with piperaquine resistance, which is mostly, but not always, explained by copy number variants in plasmepsin II and plasmepsin III ( 21 ). However, the presence of even a single isolate with both reduced sensitivity to artemisinin-based drugs in asexual and sexual stages, suggests that there is the potential that a resistant strain at treatment might be favoured for transmission to the mosquito.…”

Section: Resultssupporting

confidence: 82%

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

Witmer

Dahalan

Delves

et al. 2020

Preprint

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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

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Section: Resultssupporting

confidence: 82%

“…APS3G and APL5G both had copy number variants of mdr1 ( Table 2 ). This suggests that APS3G and APL5G will likely show resistance to mefloquine, whilst APL4G will likely show resistance to piperaquine ( 21, 24 ).…”

Section: Resultsmentioning

confidence: 99%

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

Witmer

Dahalan

Delves

et al. 2020

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“…High frequency of isolates with multiple copies of the Pfpm2 has already been reported in recent studies conducted in Cambodia (18, 20, 40). As the Vietnamese clinical sites (Gai Lai and Binh Phuoc) are located alongside the Cambodian border ( Figure 2 ), we can suspect that data from our study might reflected an evolving situation where the amplification of Pfpm2 is spreading beyond Cambodia, as described recently (5, 7).…”

Section: Discussionsupporting

confidence: 58%

“…Supporting this expectation, it seems feasible that such parasites exposed to lumefantrine as monotherapy for several days following clearance of artemether have been selected, while parasites with a single copy have been eliminated. In contrast, the low prevalence of Pfmdr1 multiple copies observed in Southeast Asia could be due to the recent implementation of DHA-PPQ, the removal of the mefloquine drug pressure or both, as the case in Cambodia (18, 20, 40).…”

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

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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.

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“…Measures of relatedness used in studies of malaria include those estimated under HMMs (hmmIBD [18], used in e.g. [19,20,21,22]; isoRelate [23], extension of XIBD [24]; DEploidIBD [25], extension of DEploid [26]). Measures based on IBS (e.g.…”

Section: Introductionmentioning

confidence: 99%

Estimating relatedness between malaria parasites

Taylor

Jacob

Neafsey

et al. 2019

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Understanding the relatedness of individuals within or between populations is a common goal in biology. Increasingly, relatedness features in genetic epidemiology studies of pathogens. These studies are relatively new compared to those in humans and other organisms, but are important for designing interventions and understanding pathogen transmission. Only recently have researchers begun to routinely apply relatedness to apicomplexan eukaryotic malaria parasites, and to date have used a range of different approaches on an ad hoc basis. It remains unclear how to compare different studies, therefore, and which measures to use. Here, we systematically compare measures based on identity-by-state and identity-by-descent using a globally diverse data set of malaria parasites, Plasmodium falciparum and Plasmodium vivax, and provide marker requirements for estimates based on identity-by-descent. We formally show that the informativeness of polyallelic markers for relatedness inference is maximised when alleles are equifrequent. Estimates based on identity-bystate are sensitive to allele frequencies, which vary across populations and by experimental design. For portability across studies, we thus recommend estimates based on identity-by-descent. To generate reliable estimates, we recommend approximately 200 biallelic or 100 polyallelic markers. Confidence intervals illuminate inference across studies based on different sets of markers. These marker requirements, unlike many thus far reported, are immediately applicable to haploid malaria parasites and other haploid eukaryotes. This is the first attempt to provide rigorous analysis of the reliability of, and requirements for, relatedness inference in malaria genetic epidemiology, and will provide a basis for statistically informed prospective study design and surveillance strategies.

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Plasmepsin II–III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum

Cited by 93 publications

References 49 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

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

Estimating relatedness between malaria parasites

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