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      Polymorphisms of the artemisinin resistant marker (K13) in Plasmodium falciparum parasite populations of Grande Comore Island 10 years after artemisinin combination therapy

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          Abstract

          Background

          Plasmodium falciparum malaria is a significant public health problem in Comoros, and artemisinin combination therapy (ACT) remains the first choice for treating acute uncomplicated P. falciparum. The emergence and spread of artemisinin-resistant P. falciparum in Southeast Asia, associated with mutations in K13-propeller gene, poses a potential threat to ACT efficacy. Detection of mutations in the P. falciparum K13-propeller gene may provide the first-hand information on changes in parasite susceptibility to artemisinin. The objective of this study is to determinate the prevalence of mutant K13-propeller gene among the P. falciparum isolates collected from Grande Comore Island, Union of Comoros, where ACT has been in use since 2004.

          Methods

          A total of 207 P. falciparum clinical isolates were collected from the island during March 2006 and October 2007 ( n = 118) and March 2013 and December 2014 ( n = 89). All isolates were analysed for single nucleotide polymorphisms (SNPs) and haplotypes in the K13-propeller gene using nested PCR and DNA sequencing.

          Results

          Only three 2006–2007 samples carried SNPs in the K13-propeller gene, one having a synonymous (G538G) and the other having two non-synonymous (S477Y and D584E) substitutions leading to two mutated haplotypes (2.2 %, 2/95). Three synonymous mutations (R471R, Y500Y, and G538G) (5.9 %, 5/85) and 7 non-synonymous substitutions (21.2 %, 18/85) with nine mutated haplotypes (18.8 %, 16/85) were found in isolates from 2013 to 2014. However, none of the polymorphisms associated with artemisinin-resistance in Southeast Asia was detected from any of the parasites examined.

          Conclusion

          This study showed increased K13-propeller gene diversity among P. falciparum populations on the Island over the course of 8 years (2006–2014). Nevertheless, none of the polymorphisms known to be associated with artemisinin resistance in Asia was detected in the parasite populations examined. Our data suggest that P. falciparum populations in Grande Comore are still effectively susceptible to artemisinin. Our results provide insights into P. falciparum populations regarding mutations in the gene associated with artemisinin resistance and will be useful for developing and updating anti-malarial guidance in Comoros.

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          Most cited references37

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          Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study

          Summary Background Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand–Myanmar (Burma) border. Methods In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms. Findings 3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5–2·7) in 2001, to 3·7 h (3·6–3·8) in 2010, compared with a mean of 5·5 h (5·2–5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≥6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010. Interpretation Genetically determined artemisinin resistance in P falciparum emerged along the Thailand–Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2–6 years. Funding The Wellcome Trust and National Institutes of Health.
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            Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum.

            Widespread use of antimalarial agents can profoundly influence the evolution of the human malaria parasite Plasmodium falciparum. Recent selective sweeps for drug-resistant genotypes may have restricted the genetic diversity of this parasite, resembling effects attributed in current debates to a historic population bottleneck. Chloroquine-resistant (CQR) parasites were initially reported about 45 years ago from two foci in southeast Asia and South America, but the number of CQR founder mutations and the impact of chlorquine on parasite genomes worldwide have been difficult to evaluate. Using 342 highly polymorphic microsatellite markers from a genetic map, here we show that the level of genetic diversity varies substantially among different regions of the parasite genome, revealing extensive linkage disequilibrium surrounding the key CQR gene pfcrt and at least four CQR founder events. This disequilibrium and its decay rate in the pfcrt-flanking region are consistent with strong directional selective sweeps occurring over only approximately 20-80 sexual generations, especially a single resistant pfcrt haplotype spreading to very high frequencies throughout most of Asia and Africa. The presence of linkage disequilibrium provides a basis for mapping genes under drug selection in P. falciparum.
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              Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia.

              The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 (K13) have been associated with resistance in vitro and in field samples from Cambodia. P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33 716 genome-wide single-nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between parasite genotypes and parasite clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance, and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread or whether they emerged independently. The presence of nonreference K13 alleles was associated with prolonged parasite clearance half-life (P = 1.97 × 10(-12)). Parasites with a mutation in any of the K13 kelch domains displayed longer parasite clearance half-lives than parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas. K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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                Author and article information

                Contributors
                huangbo198421@126.com
                dcs19811202@hotmail.com
                942966792@qq.com
                1121595778@qq.com
                wangqi198169@163.com
                thshg@126.com
                xsu@niaid.nih.gov
                liuyajun9808@126.com
                graceguangzhou@qq.com
                gyz111@hotmail.com
                xuqin@163.com
                68722514@qq.com
                466754442@qq.com
                anfanebacar@yahoo.fr
                kamalsaid2004@yahoo.fr
                rachadkeke@yahoo.fr
                amsamliva@yahoo.com
                447373997@qq.com
                489589715@qq.com
                songjpgz@sina.com
                Journal
                Parasit Vectors
                Parasit Vectors
                Parasites & Vectors
                BioMed Central (London )
                1756-3305
                15 December 2015
                15 December 2015
                2015
                : 8
                : 634
                Affiliations
                [ ]Science and Technology Park, Guangzhou University of Chinese Medicine, Guangzhou, 510006 Guangdong PR China
                [ ]School of Medicine, Jinan University, Guangzhou, 510632 Guangdong PR China
                [ ]Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 USA
                [ ]State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361005 Fujian PR China
                [ ]The first affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510006 Guangdong PR China
                [ ]Research Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006 Guangdong PR China
                [ ]Traditional Chinese Medicine Collage, Guangzhou University of Chinese Medicine, Guangzhou, 510006 Guangdong PR China
                [ ]National Malaria Control Programme, Moroni, Union of Comoros
                [ ]Ministry of Health Comoros, Moroni, Union of Comoros
                [ ]Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080 Guangdong PR China
                Article
                1253
                10.1186/s13071-015-1253-z
                4678476
                26667053
                0e4536d7-9071-415e-b21d-19c1e642ad41
                © Huang et al. 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 17 August 2015
                : 10 December 2015
                Funding
                Funded by: Natural Science Foundation of China
                Award ID: 81273643
                Award ID: 81403295
                Award Recipient :
                Funded by: International S&T Cooperation Program of China
                Award ID: 2009DFA31180
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002858, China Postdoctoral Science Foundation (CN);
                Award ID: 2015M570699
                Award Recipient :
                Funded by: Guangdong Provincial Science Foundation
                Award ID: 2015A030310107
                Award Recipient :
                Funded by: Science and Technology Program of Guangzhou
                Award ID: 2014J4500037
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2015

                Parasitology
                comoros,plasmodium falciparum,artemisinin resistance,k13-propeller,polymorphism
                Parasitology
                comoros, plasmodium falciparum, artemisinin resistance, k13-propeller, polymorphism

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