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      Limited differentiation among Plasmodium vivax populations from the northwest and to the south Pacific Coast of Colombia: A malaria corridor?

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          Abstract

          Background

          Malaria remains endemic in several countries of South America with low to moderate transmission intensity. Regional human migration through underserved endemic areas may be responsible for significant parasite dispersion making the disease resilient to interventions. Thus, the genetic characterization of malarial parasites is an important tool to assess how endemic areas may connect via the movement of infected individuals. Here, four sites in geographically separated areas reporting 80% of the malaria morbidity in Colombia were studied. The sites are located on an imaginary transect line of 1,500 km from the northwest to the south Pacific Coast of Colombia with a minimal distance of 500 km between populations that display noticeable ethnic, economic, epidemiological, and ecological differences.

          Methodology/Principal findings

          A total of 624 Plasmodium vivax samples from the four populations were genotyped by using eight microsatellite loci. Although a strong geographic structure was expected between these populations, only moderate evidence of genetic differentiation was observed using a suite of population genetic analyses. High genetic diversity, shared alleles, and low linkage disequilibrium were also found in these P. vivax populations providing no evidence for a bottleneck or clonal expansions as expected from recent reductions in the transmission that could have been the result of scaling up interventions or environmental changes. These patterns are consistent with a disease that is not only endemic in each site but also imply that there is gene flow among these populations across 1,500 km.

          Conclusion /Significance

          The observed patterns in P. vivax are consistent with a “corridor” where connected endemic areas can sustain a high level of genetic diversity locally and can restore parasite-subdivided populations via migration of infected individuals even after local interventions achieved a substantial reduction of clinical cases. The consequences of these findings in terms of control and elimination are discussed.

          Author summary

          The regional movements of infected individuals that connect suitable transmission areas make malaria resilient to control efforts. Those movements are expected to leave genetic signatures in the parasite populations that can be detected using analytical tools. In this study, the genetic makeups of Plasmodium vivax populations were characterized to assess whether the most endemic areas in Colombia were connected. Samples were collected from passive surveillance studies in four locations across an imaginary transect line of 1,500 km from the northwest to the south Pacific Coast of Colombia (South America). Considering the distance, and contrary to expectations, we found weak levels of genetic differentiation between these parasite populations with no evidence indicating that their genetic diversity has been eroded as expected whenever the prevalence of the disease is successfully reduced, e.g., through control programs or environmental changes. Although the sampling lacks the geographic and temporal detail to describe how the dispersion of parasite lineages occurred, the observed patterns are consistent with a series of infected populations that are connected in space by human movements allowing the parasite to diffuse across this 1,500 km transect. This malaria corridor needs to be characterized to achieve elimination.

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          Most cited references37

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          Global optimal eBURST analysis of multilocus typing data using a graphic matroid approach

          Background Multilocus Sequence Typing (MLST) is a frequently used typing method for the analysis of the clonal relationships among strains of several clinically relevant microbial species. MLST is based on the sequence of housekeeping genes that result in each strain having a distinct numerical allelic profile, which is abbreviated to a unique identifier: the sequence type (ST). The relatedness between two strains can then be inferred by the differences between allelic profiles. For a more comprehensive analysis of the possible patterns of evolutionary descent, a set of rules were proposed and implemented in the eBURST algorithm. These rules allow the division of a data set into several clusters of related strains, dubbed clonal complexes, by implementing a simple model of clonal expansion and diversification. Within each clonal complex, the rules identify which links between STs correspond to the most probable pattern of descent. However, the eBURST algorithm is not globally optimized, which can result in links, within the clonal complexes, that violate the rules proposed. Results Here, we present a globally optimized implementation of the eBURST algorithm – goeBURST. The search for a global optimal solution led to the formalization of the problem as a graphic matroid, for which greedy algorithms that provide an optimal solution exist. Several public data sets of MLST data were tested and differences between the two implementations were found and are discussed for five bacterial species: Enterococcus faecium, Streptococcus pneumoniae, Burkholderia pseudomallei, Campylobacter jejuni and Neisseria spp.. A novel feature implemented in goeBURST is the representation of the level of tiebreak rule reached before deciding if a link should be drawn, which can used to visually evaluate the reliability of the represented hypothetical pattern of descent. Conclusion goeBURST is a globally optimized implementation of the eBURST algorithm, that identifies alternative patterns of descent for several bacterial species. Furthermore, the algorithm can be applied to any multilocus typing data based on the number of differences between numeric profiles. A software implementation is available at .
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            PHYLOViZ: phylogenetic inference and data visualization for sequence based typing methods

            Background With the decrease of DNA sequencing costs, sequence-based typing methods are rapidly becoming the gold standard for epidemiological surveillance. These methods provide reproducible and comparable results needed for a global scale bacterial population analysis, while retaining their usefulness for local epidemiological surveys. Online databases that collect the generated allelic profiles and associated epidemiological data are available but this wealth of data remains underused and are frequently poorly annotated since no user-friendly tool exists to analyze and explore it. Results PHYLOViZ is platform independent Java software that allows the integrated analysis of sequence-based typing methods, including SNP data generated from whole genome sequence approaches, and associated epidemiological data. goeBURST and its Minimum Spanning Tree expansion are used for visualizing the possible evolutionary relationships between isolates. The results can be displayed as an annotated graph overlaying the query results of any other epidemiological data available. Conclusions PHYLOViZ is a user-friendly software that allows the combined analysis of multiple data sources for microbial epidemiological and population studies. It is freely available at http://www.phyloviz.net.
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              Malaria in Brazil, Colombia, Peru and Venezuela: current challenges in malaria control and elimination

              In spite of significant progress towards malaria control and elimination achieved in South America in the 2000s, this mosquito-transmitted tropical disease remains an important public health concern in the region. Most malaria cases in South America come from Amazon rain forest areas in northern countries, where more than half of malaria is caused by Plasmodium vivax, while Plasmodium falciparum malaria incidence has decreased in recent years. This review discusses current malaria data, policies and challenges in four South American Amazon countries: Brazil, Colombia, Peru and the Bolivarian Republic of Venezuela. Challenges to continuing efforts to further decrease malaria incidence in this region include: a significant increase in malaria cases in recent years in Venezuela, evidence of submicroscopic and asymptomatic infections, peri-urban malaria, gold mining-related malaria, malaria in pregnancy, glucose-6-phosphate dehydrogenase (G6PD) deficiency and primaquine use, and possible under-detection of Plasmodium malariae. Some of these challenges underscore the need to implement appropriate tools and procedures in specific regions, such as a field-compatible molecular malaria test, a P. malariae-specific test, malaria diagnosis and appropriate treatment as part of regular antenatal care visits, G6PD test before primaquine administration for P. vivax cases (with weekly primaquine regimen for G6PD deficient individuals), single low dose of primaquine for P. falciparum malaria in Colombia, and national and regional efforts to contain malaria spread in Venezuela urgently needed especially in mining areas. Joint efforts and commitment towards malaria control and elimination should be strategized based on examples of successful regional malaria fighting initiatives, such as PAMAFRO and RAVREDA/AMI.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: SoftwareRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                28 March 2019
                March 2019
                : 13
                : 3
                : e0007310
                Affiliations
                [1 ] Department of Biology/Institute for Genomics and Evolutionary Medicine (iGEM), Temple University, Philadelphia, Pennsylvania, United States of America
                [2 ] Department CB, University of Applied Sciences Mittweida, Mittweida, Germany
                [3 ] Caucaseco Scientific Research Center and Malaria Vaccine and Drug Development Center, Cali, Colombia
                [4 ] Faculty of Health, Universidad del Valle, Cali, Colombia
                Johns Hopkins Bloomberg School of Public Health, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-1532-3430
                Article
                PNTD-D-18-01335
                10.1371/journal.pntd.0007310
                6456216
                30921317
                956bab5f-cd5b-44ce-a26f-9abe88bf23cc
                © 2019 Pacheco et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 30 August 2018
                : 16 March 2019
                Page count
                Figures: 4, Tables: 3, Pages: 18
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: U19AI089702
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: R56AI109416
                Award Recipient :
                Funded by: Colciencias
                Award ID: 360-2011; 458-2012
                Award Recipient :
                Funded by: Colciencias
                Award ID: 719-2013
                Award Recipient :
                Funded by: Colombian Presidential Agency of International Cooperation
                Award ID: 045-2013
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100004897, Pennsylvania Department of Health;
                Award ID: TU-420721
                This work was supported by grants from the US National Institutes of Health (NIAID/ICEMR U19AI089702 to SH, R56AI109416 to AE; https://www.nih.gov/), Colciencias (360-2011 to MAH, 458-2012 to MAH, 719-2013 to SH; http://www.colciencias.gov.co/), and the Colombian Presidential Agency of International Cooperation (045-2013 to SH; http://www.apccolombia.gov.co/). This research was conducted at sites corresponding to Centro Latino Americano de Investigación en Malaria (CLAIM). Computer resources were provided by a grant from the Pennsylvania Department of Health (TU-420721). The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Organisms
                Eukaryota
                Protozoans
                Parasitic Protozoans
                Malarial Parasites
                Biology and Life Sciences
                Evolutionary Biology
                Population Genetics
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                Genetics
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                Parasitology
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                Apicomplexa
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                Malaria
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                Population Biology
                Population Genetics
                Phylogeography
                Biology and Life Sciences
                Genetics
                Heredity
                Genetic Mapping
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                Biology and Life Sciences
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                Ecology and Environmental Sciences
                Ecology
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                Custom metadata
                vor-update-to-uncorrected-proof
                2019-04-09
                All relevant data are within the manuscript and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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