Absence of Putative Artemisinin Resistance Mutations Among Plasmodium falciparum in Sub-Saharan Africa: A Molecular Epidemiologic Study

Taylor, Steve M.; Parobek, Christian M.; DeConti, Derrick K.; Kayentao, Kassoum; Coulibaly, Sheick Oumar; Greenwood, Brian; Tagbor, Harry; Williams, John T.; Bojang, Kalifa; Njie, Fanta; Desai, Meghna; Kariuki, Simon; Gutman, Julie; Mathanga, Don P.; Mårtensson, Andreas; Ngasala, Billy; Conrad, Melissa D.; Rosenthal, Philip J.; Tshefu, Antoinette; Moormann, Ann M.; Vulule, John; Doumbo, Ogobara K.; Kuile, Feiko O. ter; Meshnick, Steven R.; Bailey, Jeffrey A.; Juliano, Jonathan J.

doi:10.1093/infdis/jiu467

Cited by 263 publications

(336 citation statements)

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“…Similar observations have been made by a recent K13 genotyping study conducted in 14 African countries. 15 However, recent studies have shown a few examples of median parasite clearance half-life 5 hours in Democratic Republic of Congo and Nigeria. 11 Although factors other than parasite resistance could account for these observations, vigilant surveillance for initially low-prevalence resistance provides an important early-warning system for emerging or spreading resistance.…”

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confidence: 99%

Polymorphisms in the K13-Propeller Gene in Artemisinin-Susceptible Plasmodium falciparum Parasites from Bougoula-Hameau and Bandiagara, Mali

Ouattara¹,

Koné²,

Adams³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Abstract. Artemisinin-resistant Plasmodium falciparum malaria has been documented in southeast Asia and may already be spreading in that region. Molecular markers are important tools for monitoring the spread of antimalarial drug resistance. Recently, single-nucleotide polymorphisms (SNPs) in the PF3D7_1343700 kelch propeller (K13-propeller) domain were shown to be associated with artemisinin resistance in vivo and in vitro. The prevalence and role of K13-propeller mutations are poorly known in sub-Saharan Africa. K13-propeller mutations were genotyped by direct sequencing of nested polymerase chain reaction (PCR) amplicons from dried blood spots of pre-treatment falciparum malaria infections collected before and after the use of artemisinin-based combination therapy (ACT) as first-line therapy in Mali. Although K13-propeller mutations previously associated with delayed parasite clearance in Cambodia were not identified, 26 K13-propeller mutations were identified in both recent samples and pre-ACT infections. Parasite clearance time was comparable between infections with non-synonymous K13-propeller mutations and infections with the reference allele. These findings suggest that K13-propeller mutations are present in artemisinin-sensitive parasites and that they preceded the wide use of ACTs in Mali.

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confidence: 99%

Polymorphisms in the K13-Propeller Gene in Artemisinin-Susceptible Plasmodium falciparum Parasites from Bougoula-Hameau and Bandiagara, Mali

Ouattara¹,

Koné²,

Adams³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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100

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“…[7][8][9] Furthermore, other non-synonymous SNPs were identified in the sub-Saharan African samples that were not observed in the southeast Asian P. falciparum samples. These findings suggest that polymorphisms in the K13-propeller could vary geographically, and therefore, genetic studies on the K13-propeller in other malaria-endemic countries are needed to assess the use of this locus as a tool to monitor the global emergence and spread of artemisinin resistance.…”

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confidence: 99%

Artemisinin Resistance-Associated Polymorphisms at the K13-Propeller Locus are Absent in Plasmodium falciparum Isolates from Haiti

Carter¹,

Boulter²,

Existe³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Abstract. Antimalarial drugs are a key tool in malaria elimination programs. With the emergence of artemisinin resistance in southeast Asia, an effort to identify molecular markers for surveillance of resistant malaria parasites is underway. Non-synonymous mutations in the kelch propeller domain (K13-propeller) in Plasmodium falciparum have been associated with artemisinin resistance in samples from southeast Asia, but additional studies are needed to characterize this locus in other P. falciparum populations with different levels of artemisinin use. Here, we sequenced the K13-propeller locus in 82 samples from Haiti, where limited government oversight of non-governmental organizations may have resulted in low-level use of artemisinin-based combination therapies. We detected a single-nucleotide polymorphism (SNP) at nucleotide 1,359 in a single isolate. Our results contribute to our understanding of the global genomic diversity of the K13-propeller locus in P. falciparum populations.Discussions of global malaria elimination programs have been renewed in light of the decline in malaria-associated morbidity and mortality resulting from scaled-up vector-and parasite-targeted interventions over the past decade.1 A key strategy in malaria elimination programs is effective use of antimalarial drugs, particularly artemisinin-based combination therapies (ACTs), which are the first-line therapies in most malaria-endemic countries.1 However, malaria elimination goals face a new threat with the emergence of artemisinin resistance in southeast Asia.2-5 A recent study used both in vivo and in vitro methods to identify non-synonymous singlenucleotide polymorphisms (SNPs) at the PF3D7_1343700 kelch propeller domain (K13-propeller) in Cambodian Plasmodium falciparum associated with artemisinin resistance. 6Subsequent investigations at the K13-propeller locus in other southeast Asian populations, including those of Vietnam, Myanmar, Laos, and Thailand, confirm the association of non-synonymous SNPs at the K13-propeller with artemisinin resistance.7 However, these polymorphisms were not detected in sub-Saharan Africa P. falciparum samples from Gambia, Mali, Ghana, Burkina Faso, Congo, Democratic Republic of Congo, Kenya, Tanzania, Malawi, and Uganda, where little to no artemisinin resistance has been reported. [7][8][9] Furthermore, other non-synonymous SNPs were identified in the sub-Saharan African samples that were not observed in the southeast Asian P. falciparum samples. These findings suggest that polymorphisms in the K13-propeller could vary geographically, and therefore, genetic studies on the K13-propeller in other malaria-endemic countries are needed to assess the use of this locus as a tool to monitor the global emergence and spread of artemisinin resistance.Haiti is one of two remaining malaria-endemic countries in the Caribbean. It has several favorable elimination characteristics. 10 (1) One parasite species (P. falciparum) accounts for the majority, if not all, cases of malaria.11 (2) Malaria transmission is low.12...

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“…• studies of the distribution of polymorphisms in the field, particularly in Africa [9][10][11][12][13];…”

Section: A New Artemisinin Susceptibility Phenotype Arises In Asiamentioning

confidence: 99%

Genetic markers of artemisinin resistance in Plasmodium spp. parasites

Sutherland

2017

Emerging Topics in Life Sciences

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The vast majority of malaria patients worldwide are currently treated with combination therapy comprising one of the artemisinin family of drugs, characterised by rapid action and short plasma half-life, co-formulated with a longer-lasting drug from the amino arylalcohol or quinoline families. There is now a widely perceived threat to treatment efficacy, as reduced susceptibility to rapid artemisinin clearance in vivo has become prevalent among populations of Plasmodium falciparum in the Greater Mekong subregion since 2008. In vitro and in vivo drug selection studies, heterologous cell expression experiments and genetic epidemiology have identified many candidate markers of reduced ring-stage susceptibility to artemisinin. Certain variants of the P. falciparum pfk13 gene, which encodes a kelch domain protein implicated in the unfolded protein response, are strongly associated with slow parasite clearance by artemisinin in the Mekong subregion. However, anomalies in the epidemiological association of pfk13 variants with true treatment failure in vivo and the curious cell-cycle stage specificity of this phenotype in vitro warrant exploration in some depth. Taken together, available data suggest that the emergence of P. falciparum expressing K13 variants has not yet precipitated a public health emergency. Alternative candidate markers of artemisinin susceptibility are also described, as K13-independent treatment failure has been observed in African P. falciparum and in the rodent malaria parasite Plasmodium chabaudi.

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Absence of Putative Artemisinin Resistance Mutations Among Plasmodium falciparum in Sub-Saharan Africa: A Molecular Epidemiologic Study

Cited by 263 publications

References 28 publications

Polymorphisms in the K13-Propeller Gene in Artemisinin-Susceptible Plasmodium falciparum Parasites from Bougoula-Hameau and Bandiagara, Mali

Polymorphisms in the K13-Propeller Gene in Artemisinin-Susceptible Plasmodium falciparum Parasites from Bougoula-Hameau and Bandiagara, Mali

Artemisinin Resistance-Associated Polymorphisms at the K13-Propeller Locus are Absent in Plasmodium falciparum Isolates from Haiti

Genetic markers of artemisinin resistance in Plasmodium spp. parasites

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