Genomic analysis reveals independent evolution of Plasmodium falciparum populations in Ethiopia

Abstract Background Plasmodium falciparum parasite populations in Ethiopia have been experiencing local selective pressures from drugs and immunity, leading to evolutionary adaptation. However, there was a paucity of data on genomic characterization and evolutionary adaptations of P. falciparum isolates from the central area of Ethiopia. Methods Whole-genome analysis of 25 P. falciparum isolates from central Ethiopia, specifically from West Arsi, were studied to determine their genetic diversity, population structures, and signatures of selection in known drug resistance alleles against global isolates from Cambodia, Thailand, DR Congo, and Malawi. Results A total of 18,517 high-quality single-nucleotide polymorphisms (SNPs) were identified in Ethiopian P. falciparum isolates. About 84% of the Ethiopian P. falciparum isolates had a FWS value > 0.95 showing a dominant single genotype infection in most isolates at the time of collection with little potential for out-crossing as expected in areas with low transmission intensity. Within-host diversity of Ethiopian infections was significantly different from East African (p < 0.001), but not Southeast Asian infections (P > 0.05). A significant population structure has been observed by PCA and population differentiation between Ethiopian parasites and East African (Fst ~ 10%) and Southeast Asian populations (Fst ~ 18%), suggesting limited gene flow and the independent evolution of the Ethiopian parasite population. Moreover, a total of 125 genes under balancing selection was found that include ama1, trap, eba175, and lsa3, previously identified as targets of human host immunity. Recent directional selection analysis using integrated standardized haplotype score (IHS) did not detect any selection signatures in the Pfcrt, Pfdhfr, Pfdhps, Pfmdr1, and PfK13 genes. However, known drug resistance-conferring mutations analysis showed that at least one SNP marker was fixed in these genes, but not in Pfdhps and PfK13. Conclusion Plasmodium falciparum populations in the central region of Ethiopia was structurally diverged from both Southeast Asian and other East African populations. Malaria infections in Ethiopia had low within-host diversity, and parasites carry fixed chloroquine resistance markers despite the withdrawal of this drug for the treatment of P. falciparum.

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Genomic analysis reveals independent evolution of Plasmodium falciparum populations in Ethiopia

10.21203/rs.3.rs-75436/v2 ◽

2021 ◽

Author(s):

Deriba Abera Beyene ◽

Caleb Kipkurui Kibet ◽

Teshome Degefa ◽

Lucas Amenga-Etego ◽

Joel L Bargul ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Balancing Selection ◽

Central Area ◽

Southeast Asian ◽

Chloroquine Resistance ◽

East African ◽

Whole Genome Analysis ◽

Host Diversity ◽

Independent Evolution

Abstract Background: Plasmodium falciparumparasite populations in Ethiopia have been experiencing local selective pressures from drugs and immunity, leading to evolutionary adaptation. However, there wasthe paucity of data on the genomic characterization and the evolutionary adaptations of P. falciparum isolates from the central area of Ethiopia. Method: Whole-genome analysis of 25 P. falciparum isolates from central Ethiopia, specifically from West Arsi, were studied to determine theirgenetic diversity, population structures, and signatures of selection in known drug resistance alleles against global isolates from Cambodia, Thailand, DR Congo, and Malawi.Result: A total of 18,517high-quality single-nucleotide polymorphisms (SNPs) were identifiedin Ethiopian P. falciparum isolates.About 84% of the Ethiopian P. falciparum isolates hadan FWS value >0.95showing a dominant single genotype infection in most isolates at the time of collection with little potential for out-crossing as expected in areaswith low transmission intensity. Within host diversity of Ethiopian infectionswas significantly differentfrom East African (p < 0.001) but not Southeast Asian infections (P >0.05). We observed significant population structureby PCA andpopulation differentiation between Ethiopian parasitesand East Africa (Fst~ 10%) and Southeast Asia populations (Fst ~18%), suggesting limited gene flow and the independent evolution of the Ethiopian parasite population. Moreover, we found a total of 125 genes under balancing selection that includedama1, trap, eba175, and lsa3previously identified as targets of human host immunity. Recent directional selection analysis using integrated standardized haplotype score (IHS) did not detect any selection signatures in the Pfcrt,Pfdhfr,Pfdhps, Pfmdr1, and PfK13 genes. However, known drug resistance-conferring mutations analysis showed that at least one SNP marker was fixed in these genes, but not in Pfdhps and PfK13.Conclusion: Plasmodium falciparumpopulation in the central region of Ethiopia wasstructurally diverged from both Southeast Asian and other East African populations. Malaria infections in Ethiopia had low within-host diversity, and parasites carryfixed chloroquine resistance markers despite the withdrawal of this drug for the treatment of P. falciparum.

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Genomic analysis reveals independent evolution of Plasmodium falciparum population in Ethiopia

10.21203/rs.3.rs-75436/v1 ◽

2020 ◽

Author(s):

Deriba Abera ◽

Caleb Kipkurui Kibet ◽

Teshome Degefa ◽

Lucas Amenga-Etego ◽

Joel L Bargul ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Balancing Selection ◽

Central Area ◽

Southeast Asian ◽

Chloroquine Resistance ◽

Nucleotide Polymorphisms ◽

East African ◽

Whole Genome Analysis ◽

Host Diversity ◽

Independent Evolution

Abstract Background Plasmodium falciparum parasite populations have been experiencing local selective pressures from drugs and immunity, leading to evolutionary adaptation. However, there was paucity of data on the genomic characterization and the evolutionary adaptations of P. falciparum isolates from central area of Ethiopia. Method : Whole genome analysis of 25 P. falciparum isolates from central Ethiopia were made to determine their genetic diversity, population structures and signatures of selection in known drug resistance loci against isolates from Cambodia, Thailand, DR Congo and Malawi. Result A total of 18,517 high-quality single-nucleotide polymorphisms (SNPs) were identified with average nucleotide diversity (π = 0.00022) across the genome. About 84% of the Ethiopian P. falciparum isolates had FWS value > 0.95 showing a dominant single genotype infection in most isolates at the time of collection with little potential for out-crossing as expected in areas with low transmission intensity. Within host diversity of Ethiopian infections was significantly different from East African (p < 0.001) but not Southeast Asian infections (P > 0.05). A significant population structure differentiation between Ethiopian parasites and East Africa (Fst < 10%) and Southeast Asia populations (Fst ~ 18%) has been observed, suggesting limited gene flow and the independent evolution of the Ethiopian parasite population. Moreover, a total of 125 genes under balancing selection is identified that included ama1, trap, eba175, and lsa3 previously identified as targets of human host immunity. Recent directional selection analysis using integrated standardized haplotype score (IHS) did not detect any selection signatures in the pfcrt, pfdhfr, pfdhps, pfmdr1, and pfK13 genes. However, mutations analysis showed that at least one SNP marker was fixed in these genes, but not in pfdhps and pfK13. Conclusion Plasmodium falciparum population in central region of Ethiopia were structurally diverged from both southeast Asian and other East African populations. A low within host diversity is noted among the Ethiopian parasites. Indeed, the parasites carry fixed chloroquine resistance markers despite the withdrawal of this drug for the treatment of P. falciparum.

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Local differentiation in Plasmodium falciparum drug resistance genes in Sudan

Parasitology ◽

10.1017/s0031182003003020 ◽

2003 ◽

Vol 126 (5) ◽

pp. 391-400 ◽

Cited By ~ 88

Author(s):

A. A. ABDEL-MUHSIN ◽

M. J. MACKINNON ◽

P. AWADALLA ◽

E. ALI ◽

S. SULEIMAN ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Population Structure ◽

Resistance Genes ◽

Microsatellite Loci ◽

Balancing Selection ◽

Dry Season ◽

Chloroquine Resistance ◽

Multi Drug Resistance ◽

Eastern Region

Studies of population genetic structure of parasites can be used to infer which parasite genes are under selection. Here, the population structure of 4 genes associated with drug resistance of Plasmodium falciparum (the chloroquine resistance transporter, pfcrt, dihydrofolate reductase, dhfr, dihydropteroate synthase, dhps, and multi-drug resistance, pfmdr-1) were examined in parasite populations in 3 villages in eastern Sudan and in an urban area of Khartoum, the capital. In order to differentiate the effects of drug selection from neutral influences on population structure, parasites were also genotyped for 3 putatively neutral microsatellite loci (polyα, TA81 and pfg377), and for 2 antigenic loci that are either under balancing selection or neutral, merozoite surface protein 1 and 2, (MSP-1 and MSP-2). Cross-sectional surveys were carried out during the peak transmission (wet) season and in the ensuing dry season. No significant variation in frequencies of MSP-1 and MSP-2 alleles was seen among villages in the eastern region and between the villages and Khartoum, nor between the wet and dry season. However, the drug resistance genes, pfmdr-1, pfcrt and dhfr and to a lesser extent the microsatellite loci showed high FST values when comparing villages with Khartoum, indicating strong geographical differentiation at these loci. Moreover, variation in frequencies of the drug resistance genes, pfmdr-1, pfcrt and dhfr, was observed between the wet and dry season. These differences most probably reflect the variation in drug pressure between each region, and in drug usage between the wet and dry season in a given region.

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Piperaquine resistant Cambodian Plasmodium falciparum clinical isolates: in vitro genotypic and phenotypic characterization

10.21203/rs.3.rs-22444/v3 ◽

2020 ◽

Author(s):

Nonlawat Boonyalai ◽

Brian A Vesely ◽

Chatchadaporn Thamnurak ◽

Chantida Praditpol ◽

Watcharintorn Fagnark ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Copy Number ◽

Drug Susceptibility ◽

Antagonistic Activity ◽

Drug Combinations ◽

Chloroquine Resistance ◽

Phenotypic Characterization ◽

Field Isolates

Abstract Background High rates of dihydroartemisinin-piperaquine (DHA-PPQ) treatment failures have been documented for uncomplicated Plasmodium falciparum in Cambodia. The genetic markers plasmepsin 2 ( pfpm2 ), exonuclease ( pfexo ) and chloroquine resistance transporter ( pfcrt ) genes are associated with PPQ resistance and are used for monitoring the prevalence of drug resistance and guiding malaria drug treatment policy.Methods To examine the relative contribution of each marker to PPQ resistance, in vitro culture and the PPQ survival assay were performed on seventeen P. falciparum isolates from northern Cambodia, and the presence of E415G-Exo and pfcrt mutations (T93S, H97Y, F145I, I218F, M343L, C350R, and G353V) as well as pfpm2 copy number polymorphisms were determined. Parasites were then cloned by limiting dilution and the cloned parasites were tested for drug susceptibility. Isobolographic analysis of several drug combinations for standard clones and newly cloned P. falciparum Cambodian isolates was also determined.Results The characterization of culture-adapted isolates revealed that the presence of novel pfcrt mutations (T93S, H97Y, F145I, and I218F) with E415G-Exo mutation can confer PPQ-resistance, in the absence of pfpm2 amplification. In vitro testing of PPQ resistant parasites demonstrated a bimodal dose-response, the existence of a swollen digestive vacuole phenotype, and an increased susceptibility to quinine, chloroquine, mefloquine and lumefantrine. To further characterize drug sensitivity, parental parasites were cloned in which a clonal line, 14-B5, was identified as sensitive to artemisinin and piperaquine, but resistant to chloroquine. Assessment of the clone against a panel of drug combinations revealed antagonistic activity for six different drug combinations. However, mefloquine-proguanil and atovoquone-proguanil combinations revealed synergistic antimalarial activity.Conclusions Surveillance for PPQ resistance in regions relying on DHA-PPQ as the first-line treatment is dependent on the monitoring of molecular markers of drug resistance. P. falciparum harbouring novel pfcrt mutations with E415G-exo mutations displayed PPQ resistant phenotype. The presence of pfpm2 amplification was not required to render parasites PPQ resistant suggesting that the increase in pfpm2 copy number alone is not the sole modulator of PPQ resistance. Genetic background of circulating field isolates appear to play a role in drug susceptibility and biological responses induced by drug combinations. The use of latest field isolates may be necessary for assessment of relevant drug combinations against P. falciparum strains and when down-selecting novel drug candidates.

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Prevalence of chloroquine and antifolate drug resistance alleles in Plasmodium falciparum clinical isolates from three areas in Ghana

AAS Open Research ◽

10.12688/aasopenres.12825.1 ◽

2018 ◽

Vol 1 ◽

pp. 1 ◽

Cited By ~ 2

Author(s):

James Abugri ◽

Felix Ansah ◽

Kwaku P. Asante ◽

Comfort N. Opoku ◽

Lucas A. Amenga-Etego ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Chloroquine Resistance ◽

Published Data ◽

Nucleotide Polymorphisms ◽

Triple Mutant ◽

Chloroquine Resistance Transporter ◽

Significant Difference ◽

Quadruple Mutant ◽

Study Sites

Background: The emergence and spread of resistance in Plasmodium falciparum to chloroquine (CQ) and the antifolate drug sulfadoxine-pyrimethamine (SP) necessitated the change from CQ to artemisinin-based combination therapies (ACTs) as first-line drug for the management of uncomplicated malaria in Ghana in 2005. Methods: To examine the prevalence of molecular markers associated with CQ and antifolate drug resistance in Ghana, we genotyped single nucleotide polymorphisms (SNPs) in the P. falciparum chloroquine resistance transporter (pfcrt, PF3D7_0709000), multidrug resistance (pfmdr1, PF3D7_0523000), bifunctional dihydrofolate reductase-thymidylate synthase (pfdhfr, PF3D7_0417200) and dihydropteroate synthase (pfdhps, PF3D7_0810800) genes in children with malaria reporting to hospitals in three different epidemiological areas of Ghana (Accra, Kintampo and Navrongo) between 2012 and 2017. Results: The overall prevalence of the CQ resistance-associated pfcrt 76T allele was 8%, whereas pfmdr1 86Y and 184F alleles were present in 10% and 65% of infections respectively. Most of the isolates harboured the antifolate resistance-associated pfdhfr 51I, 59R and 108N alleles, including 68% of them with the triple mutant pfdhfr I51R59N108 combination. Pfdhps 437G and 540E were detected in 90.6% and 0.7% of infections, respectively. We observed no significant difference across the three study sites for all the polymorphisms except for pfdhps 437G, which was more common in Accra than at the other sites. Across both pfdhfr and pfdhps genes, a large proportion (61%) of the isolates harboured the quadruple mutant combination (I51R59N108/G437). Conclusion: Comparison of the present results to previously published data shows a significant decrease in the prevalence of CQ resistance alleles during the 12 years after CQ withdrawal, but an increase in the alleles that mediate SP resistance, which could be due to the continuous use of antifolate drugs for prophylaxis.

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A seven-year surveillance of epidemiology of malaria reveals travel and gender are the key drivers of dispersion of drug resistant genotypes in Kenya

PeerJ ◽

10.7717/peerj.8082 ◽

2020 ◽

Vol 8 ◽

pp. e8082

Author(s):

Moureen Maraka ◽

Hoseah M. Akala ◽

Asito S. Amolo ◽

Dennis Juma ◽

Duke Omariba ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Reference Group ◽

Multivariate Model ◽

Chloroquine Resistance ◽

Health Concern ◽

Univariate Model ◽

And Gender ◽

Resistant Genotypes

Malaria drug resistance is a global public health concern. Though parasite mutations have been associated with resistance, other factors could influence the resistance. A robust surveillance system is required to monitor and help contain the resistance. This study established the role of travel and gender in dispersion of chloroquine resistant genotypes in malaria epidemic zones in Kenya. A total of 1,776 individuals presenting with uncomplicated malaria at hospitals selected from four malaria transmission zones in Kenya between 2008 and 2014 were enrolled in a prospective surveillance study assessing the epidemiology of malaria drug resistance patterns. Demographic and clinical information per individual was obtained using a structured questionnaire. Further, 2 mL of blood was collected for malaria diagnosis, parasitemia quantification and molecular analysis. DNA extracted from dried blood spots collected from each of the individuals was genotyped for polymorphisms in Plasmodium falciparum chloroquine transporter gene (Pfcrt 76), Plasmodium falciparum multidrug resistant gene 1 (Pfmdr1 86 and Pfmdr1 184) regions that are putative drug resistance genes using both conventional polymerase chain reaction (PCR) and real-time PCR. The molecular and demographic data was analyzed using Stata version 13 (College Station, TX: StataCorp LP) while mapping of cases at the selected geographic zones was done in QGIS version 2.18. Chloroquine resistant (CQR) genotypes across gender revealed an association with chloroquine resistance by both univariate model (p = 0.027) and by multivariate model (p = 0.025), female as reference group in both models. Prior treatment with antimalarial drugs within the last 6 weeks before enrollment was associated with carriage of CQR genotype by multivariate model (p = 0.034). Further, a significant relationship was observed between travel and CQR carriage both by univariate model (p = 0.001) and multivariate model (p = 0.002). These findings suggest that gender and travel are significantly associated with chloroquine resistance. From a gender perspective, males are more likely to harbor resistant strains than females hence involved in strain dispersion. On the other hand, travel underscores the role of transport network in introducing spread of resistant genotypes, bringing in to focus the need to monitor gene flow and establish strategies to minimize the introduction of resistance strains by controlling malaria among frequent transporters.

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Prevalence of chloroquine and antifolate drug resistance alleles in Plasmodium falciparum clinical isolates from three areas in Ghana

AAS Open Research ◽

10.12688/aasopenres.12825.2 ◽

2018 ◽

Vol 1 ◽

pp. 1

Author(s):

James Abugri ◽

Felix Ansah ◽

Kwaku P. Asante ◽

Comfort N. Opoku ◽

Lucas A. Amenga-Etego ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Intermittent Preventive Treatment ◽

Preventive Treatment ◽

Chloroquine Resistance ◽

Nucleotide Polymorphisms ◽

Chloroquine Resistance Transporter ◽

Significant Difference ◽

Quadruple Mutant ◽

Study Sites

Background: The emergence and spread of resistance in Plasmodium falciparum to chloroquine (CQ) necessitated the change from CQ to artemisinin-based combination therapies (ACTs) as first-line drug for the management of uncomplicated malaria in Ghana in 2005. Sulphadoxine-pyrimethamine (SP) which was the second line antimalarial drug in Ghana, was now adopted for intermittent preventive treatment of malaria in pregnancy (IPTp). Methods: To examine the prevalence of molecular markers associated with CQ and antifolate drug resistance in Ghana, we employed restriction fragment length polymorphism polymerase chain reaction to genotype and compare single nucleotide polymorphisms (SNPs) in the P. falciparum chloroquine resistance transporter ( pfcrt, PF3D7_0709000), multidrug resistance ( pfmdr1, PF3D7_0523000), bifunctional dihydrofolate reductase-thymidylate synthase ( pfdhfr, PF3D7_0417200) and dihydropteroate synthase ( pfdhps, PF3D7_0810800) genes. Parasites were collected from children with malaria reporting to hospitals in three different epidemiological areas of Ghana (Accra, Kintampo and Navrongo) in 2012-2013 and 2016-2017. Results: The overall prevalence of the CQ resistance-associated pfcrt 76T allele was 8%, whereas pfmdr1 86Y and 184F alleles were present in 10.2% and 65.1% of infections, respectively. The majority of the isolates harboured the antifolate resistance-associated pfdhfr alleles 51I (83.4%), 59R (85.9 %) and 108N (90.5%). Pfdhps 437G and 540E were detected in 90.6% and 0.7% of infections, respectively. We observed no significant difference across the three study sites for all the polymorphisms except for pfdhps 437G, which was more common in Accra compared to Kintampo for the 2016-2017 isolates. Across both pfdhfr and pfdhps genes, a large proportion (61%) of the isolates harboured the quadruple mutant combination (I 51 R 59 N 108/ G 437). CQ resistance alleles decreased during the 12 years after CQ withdrawal, but an mediate SP resistance alleles increased. Conclusion: Surveillance of the prevalence of resistance alleles is necessary in monitoring the efficacy of antimalarial drugs.

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3-Halo Chloroquine Derivatives Overcome Plasmodium falciparum Chloroquine Resistance Transporter-Mediated Drug Resistance in P. falciparum

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01139-15 ◽

2015 ◽

Vol 59 (12) ◽

pp. 7891-7893 ◽

Cited By ~ 2

Author(s):

Sonia Edaye ◽

Dagobert Tazoo ◽

D. Scott Bohle ◽

Elias Georges

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Chloroquine Resistance ◽

Content Type ◽

Chloroquine Resistance Transporter ◽

Highly Effective

ABSTRACTPolymorphism in thePlasmodium falciparumchloroquine resistance transporter (PfCRT) was shown to cause chloroquine resistance. In this report, we examined the antimalarial potential of novel 3-halo chloroquine derivatives (3-chloro, 3-bromo, and 3-iodo) against chloroquine-susceptible and -resistantP. falciparum. All three derivatives inhibited the proliferation ofP. falciparum; with 3-iodo chloroquine being most effective. Moreover, 3-iodo chloroquine was highly effective at potentiating and reversing chloroquine toxicity of drug-susceptible and -resistantP. falciparum.

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A comprehensive analysis of drug resistance molecular markers and Plasmodium falciparum genetic diversity in two malaria endemic sites in Mali

Malaria Journal ◽

10.1186/s12936-019-2986-5 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 4

Author(s):

Seidina A. S. Diakité ◽

Karim Traoré ◽

Ibrahim Sanogo ◽

Taane G. Clark ◽

Susana Campino ◽

...

Keyword(s):

Genetic Diversity ◽

Drug Resistance ◽

Plasmodium Falciparum ◽

Molecular Markers ◽

Malaria Transmission ◽

Resistance Gene ◽

Artemisinin Resistance ◽

Chloroquine Resistance ◽

Malaria Control Programme ◽

Codon Substitution

Abstract Background Drug resistance is one of the greatest challenges of malaria control programme in Mali. Recent advances in next-generation sequencing (NGS) technologies provide new and effective ways of tracking drug-resistant malaria parasites in Africa. The diversity and the prevalence of Plasmodium falciparum drug-resistance molecular markers were assessed in Dangassa and Nioro-du-Sahel in Mali, two sites with distinct malaria transmission patterns. Dangassa has an intense seasonal malaria transmission, whereas Nioro-du-Sahel has an unstable and short seasonal malaria transmission. Methods Up to 270 dried blood spot samples (214 in Dangassa and 56 in Nioro-du-Sahel) were collected from P. falciparum positive patients in 2016. Samples were analysed on the Agena MassARRAY® iPLEX platform. Specific codons were targeted in Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps, Pfarps10, Pfferredoxin, Pfexonuclease and Pfmdr2 genes. The Sanger’s 101-SNPs-barcode method was used to assess the genetic diversity of P. falciparum and to determine the parasite species. Results The Pfcrt_76T chloroquine-resistance genotype was found at a rate of 64.4% in Dangassa and 45.2% in Nioro-du-Sahel (p = 0.025). The Pfdhfr_51I-59R-108N pyrimethamine-resistance genotype was 14.1% and 19.6%, respectively in Dangassa and Nioro-du-Sahel. Mutations in the Pfdhps_S436-A437-K540-A581-613A sulfadoxine-resistance gene was significantly more prevalent in Dangassa as compared to Nioro-du-Sahel (p = 0.035). Up to 17.8% of the isolates from Dangassa vs 7% from Nioro-du-Sahel harboured at least two codon substitutions in this haplotype. The amodiaquine-resistance Pfmdr1_N86Y mutation was identified in only three samples (two in Dangassa and one in Nioro-du-Sahel). The lumefantrine-reduced susceptibility Pfmdr1_Y184F mutation was found in 39.9% and 48.2% of samples in Dangassa and Nioro-du-Sahel, respectively. One piperaquine-resistance Exo_E415G mutation was found in Dangassa, while no artemisinin resistance genetic-background were identified. A high P. falciparum diversity was observed, but no clear genetic aggregation was found at either study sites. Higher multiplicity of infection was observed in Dangassa with both COIL (p = 0.04) and Real McCOIL (p = 0.02) methods relative to Nioro-du-Sahel. Conclusions This study reveals high prevalence of chloroquine and pyrimethamine-resistance markers as well as high codon substitution rate in the sulfadoxine-resistance gene. High genetic diversity of P. falciparum was observed. These observations suggest that the use of artemisinins is relevant in both Dangassa and Nioro-du-Sahel.

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Genetic Variations Associated with Drug Resistance Markers in Asymptomatic Plasmodium falciparum Infections in Myanmar

Genes ◽

10.3390/genes10090692 ◽

2019 ◽

Vol 10 (9) ◽

pp. 692 ◽

Cited By ~ 5

Author(s):

Yan Zhao ◽

Ziling Liu ◽

Myat Thu Soe ◽

Lin Wang ◽

Than Naing Soe ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Multidrug Resistance ◽

Point Mutations ◽

Multidrug Resistant ◽

Genetic Variations ◽

Chloroquine Resistance ◽

Geographically Dispersed ◽

Resistance Markers ◽

Asymptomatic Infections

The emergence and spread of drug resistance is a problem hindering malaria elimination in Southeast Asia. In this study, genetic variations in drug resistance markers of Plasmodium falciparum were determined in parasites from asymptomatic populations located in three geographically dispersed townships of Myanmar by PCR and sequencing. Mutations in dihydrofolate reductase (pfdhfr), dihydropteroate synthase (pfdhps), chloroquine resistance transporter (pfcrt), multidrug resistance protein 1 (pfmdr1), multidrug resistance-associated protein 1 (pfmrp1), and Kelch protein 13 (k13) were present in 92.3%, 97.6%, 84.0%, 98.8%, and 68.3% of the parasites, respectively. The pfcrt K76T, pfmdr1 N86Y, pfmdr1 I185K, and pfmrp1 I876V mutations were present in 82.7%, 2.5%, 87.5%, and 59.8% isolates, respectively. The most prevalent haplotypes for pfdhfr, pfdhps, pfcrt and pfmdr1 were 51I/59R/108N/164L, 436A/437G/540E/581A, 74I/75E/76T/220S/271E/326N/356T/371I, and 86N/130E/184Y/185K/1225V, respectively. In addition, 57 isolates had three different point mutations (K191T, F446I, and P574L) and three types of N-terminal insertions (N, NN, NNN) in the k13 gene. In total, 43 distinct haplotypes potentially associated with multidrug resistance were identified. These findings demonstrate a high prevalence of multidrug-resistant P. falciparum in asymptomatic infections from diverse townships in Myanmar, emphasizing the importance of targeting asymptomatic infections to prevent the spread of drug-resistant P. falciparum.

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