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

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          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.

          Electronic supplementary material

          The online version of this article (10.1186/s12936-017-2140-1) contains supplementary material, which is available to authorized users.

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          Most cited references 38

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          The role of Atg proteins in autophagosome formation.

          Macroautophagy is mediated by a unique organelle, the autophagosome, which encloses a portion of cytoplasm for delivery to the lysosome. Autophagosome formation is dynamically regulated by starvation and other stresses and involves complicated membrane reorganization. Since the discovery of yeast Atg-related proteins, autophagosome formation has been dissected at the molecular level. In this review we describe the molecular mechanism of autophagosome formation with particular focus on the function of Atg proteins and the long-standing discussion regarding the origin of the autophagosome membrane.
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            Discovery of gene function by expression profiling of the malaria parasite life cycle.

            The completion of the genome sequence for Plasmodium falciparum, the species responsible for most malaria human deaths, has the potential to reveal hundreds of new drug targets and proteins involved in pathogenesis. However, only approximately 35% of the genes code for proteins with an identifiable function. The absence of routine genetic tools for studying Plasmodium parasites suggests that this number is unlikely to change quickly if conventional serial methods are used to characterize encoded proteins. Here, we use a high-density oligonucleotide array to generate expression profiles of human and mosquito stages of the malaria parasite's life cycle. Genes with highly correlated levels and temporal patterns of expression were often involved in similar functions or cellular processes.
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              Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum.

              Multilocus genotyping of microbial pathogens has revealed a range of population structures, with some bacteria showing extensive recombination and others showing almost complete clonality. The population structure of the protozoan parasite Plasmodium falciparum has been harder to evaluate, since most studies have used a limited number of antigen-encoding loci that are known to be under strong selection. We describe length variation at 12 microsatellite loci in 465 infections collected from 9 locations worldwide. These data reveal dramatic differences in parasite population structure in different locations. Strong linkage disequilibrium (LD) was observed in six of nine populations. Significant LD occurred in all locations with prevalence <1% and in only two of five of the populations from regions with higher transmission intensities. Where present, LD results largely from the presence of identical multilocus genotypes within populations, suggesting high levels of self-fertilization in populations with low levels of transmission. We also observed dramatic variation in diversity and geographical differentiation in different regions. Mean heterozygosities in South American countries (0.3-0.4) were less than half those observed in African locations (0. 76-0.8), with intermediate heterozygosities in the Southeast Asia/Pacific samples (0.51-0.65). Furthermore, variation was distributed among locations in South America (F:(ST) = 0.364) and within locations in Africa (F:(ST) = 0.007). The intraspecific patterns of diversity and genetic differentiation observed in P. falciparum are strikingly similar to those seen in interspecific comparisons of plants and animals with differing levels of outcrossing, suggesting that similar processes may be involved. The differences observed may also reflect the recent colonization of non-African populations from an African source, and the relative influences of epidemiology and population history are difficult to disentangle. These data reveal a range of population structures within a single pathogen species and suggest intimate links between patterns of epidemiology and genetic structure in this organism.
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                Author and article information

                Contributors
                aankitddwivedi@gmail.com , adwivedi@som.umaryland.edu
                christelle.reynes@umontpellier.fr
                axel.kuehn@inserm.fr
                danielbarryroche@gmail.com
                knimol@pasteur-kh.org
                maxime.hebrard@riken.jp
                sylvain.milanesi@lirmm.fr
                rivals@lirmm.fr
                frutossmt@gmail.com
                dmenard@pasteur.fr
                choukri.benmamoun@yale.edu
                jacques.colinge@inserm.fr
                emmanuel.cornillot@umontpellier.fr
                Journal
                Malar J
                Malar. J
                Malaria Journal
                BioMed Central (London )
                1475-2875
                19 December 2017
                19 December 2017
                2017
                : 16
                Affiliations
                [1 ]ISNI 0000 0001 2097 0141, GRID grid.121334.6, Institut de Biologie Computationnelle (IBC), ; 34095 Montpellier, France
                [2 ]Institut de Recherche en Cancérologie de Montpellier, Institut régional du Cancer Montpellier & Université de Montpellier, IRCM-INSERM U1194, 34298 Montpellier, France
                [3 ]ISNI 0000 0001 2097 0141, GRID grid.121334.6, Laboratoire de Biostatistiques, Informatique et Physique Pharmaceutique, UFR Pharmacie, , Université de Montpellier, ; 34093 Montpellier, France
                [4 ]ISNI 0000 0004 0383 2080, GRID grid.461890.2, Institut de Génomique Fonctionnelle-CNRS, ; 34094 Montpellier, France
                [5 ]Centre de Recherche en Biologie cellulaire de Montpellier, CNRS-UMR 5237, 34293 Montpellier, France
                [6 ]GRID grid.418537.c, Malaria Molecular Epidemiology Unit, , Institut Pasteur du Cambodge, ; Phnom Penh, Cambodia
                [7 ]ISNI 0000 0001 2097 0141, GRID grid.121334.6, Laboratoire d’informatique, de robotique et de microélectronique de Montpellier, LIRMM, CNRS, , Université de Montpellier, ; 34095 Montpellier, France
                [8 ]ISNI 0000000094465255, GRID grid.7597.c, Present Address: Center for Integrative Medical Sciences, , RIKEN, ; Yokohama, Kanagawa Japan
                [9 ]ISNI 0000 0001 2153 9871, GRID grid.8183.2, CIRAD, UMR Intertryp, ; 34398 Montpellier, France
                [10 ]ISNI 0000 0001 2097 0141, GRID grid.121334.6, IES, UMR 5214, , Université de Montpellier, CNRS, ; 34095 Montpellier, France
                [11 ]ISNI 0000 0001 2353 6535, GRID grid.428999.7, Present Address: Biology of Host-Parasite Interactions Unit, , Institut Pasteur, ; Paris, France
                [12 ]ISNI 0000000419368710, GRID grid.47100.32, Section of Infectious Diseases, Department of Internal Medicine, , Yale School of Medicine, ; New Haven, CT 06520 USA
                [13 ]ISNI 0000 0001 2175 4264, GRID grid.411024.2, Present Address: Institute for Genome Sciences, , University of Maryland School of Medicine, ; Baltimore, MD 21201 USA
                Article
                2140
                10.1186/s12936-017-2140-1
                5735551
                © The Author(s) 2017

                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.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001665, Agence Nationale de la Recherche;
                Award ID: ANR-11-BINF-0002
                Award Recipient :
                Funded by: ERASMUS MUNDUS SVAGATA
                Award ID: 2012 – 2648/ 001-001
                Award Recipient :
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                © The Author(s) 2017

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