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    Functional analysis of Plasmodium falciparum subpopulations associated with artemisinin resistance in Cambodia

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    Author
    Dwivedi, A.
    Reynes, C.
    Kuehn, A.
    Date
    2017
    Journal
    Malaria Journal
    Publisher
    BioMed Central Ltd.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://www.doi.org/10.1186/s12936-017-2140-1
    Abstract
    Background: Plasmodium falciparum malaria is one of the most widespread parasitic infections in humans and remains a leading global health concern. Malaria elimination efforts are threatened by the emergence and spread of resistance to artemisinin-based combination therapy, the first-line treatment of malaria. Promising molecular markers and pathways associated with artemisinin drug resistance have been identified, but the underlying molecular mechanisms of resistance remains unknown. The genomic data from early period of emergence of artemisinin resistance (2008-2011) was evaluated, with aim to define k13 associated genetic background in Cambodia, the country identified as epicentre of anti-malarial drug resistance, through characterization of 167 parasite isolates using a panel of 21,257 SNPs. Results: Eight subpopulations were identified suggesting a process of acquisition of artemisinin resistance consistent with an emergence-selection-diffusion model, supported by the shifting balance theory. Identification of population specific mutations facilitated the characterization of a core set of 57 background genes associated with artemisinin resistance and associated pathways. The analysis indicates that the background of artemisinin resistance was not acquired after drug pressure, rather is the result of fixation followed by selection on the daughter subpopulations derived from the ancestral population. Conclusions: Functional analysis of artemisinin resistance subpopulations illustrates the strong interplay between ubiquitination and cell division or differentiation in artemisinin resistant parasites. The relationship of these pathways with the P. falciparum resistant subpopulation and presence of drug resistance markers in addition to k13, highlights the major role of admixed parasite population in the diffusion of artemisinin resistant background. The diffusion of resistant genes in the Cambodian admixed population after selection resulted from mating of gametocytes of sensitive and resistant parasite populations. Copyright 2017 The Author(s).
    Sponsors
    DBR and EC were supported by the ANR (Agence Nationale de la Recherche “Investissements d’avenir/Bioinformatique”): ANR-11-BINF-0002 (Institut de Biologie Computationnelle). AD was funded by Erasmus Mundus Action 2: Svaagata.eu project: India, funded by the European Commission (ref.nr Agreement Number: 2012-2648/001-001-EM Action 2-Partnerships).
    Keyword
    Admixed subpopulations
    Artemisinin resistance
    Cambodia
    k13
    Malaria
    Network based stratification
    Plasmodium falciparum
    Population fragmentation
    Redox metabolism
    Shifting balance theory
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85038437838&doi=10.1186%2fs12936-017-2140-1&partnerID=40&md5=576f7986c0b22c682b2272afd38d8e6a; http://hdl.handle.net/10713/9921
    ae974a485f413a2113503eed53cd6c53
    10.1186/s12936-017-2140-1
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