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      Evidence for Novel Hepaciviruses in Rodents

      1 , 1 , 1 , 2 , 2 , 3 , 4 , 5 , 1 , 6 , 6 , 1 , 7 , 1 , 8 , 1 , 9 , 10 , 10 , 11 , 12 , 13 , 14 , 1 , 15 , 16 , 17 , 7 , 18 , 18 , 19 , 12 , 20 , 13 , 6 , 21 , 22 , 23 , 14 , 1 , *

      PLoS Pathogens

      Public Library of Science

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          Hepatitis C virus (HCV) is among the most relevant causes of liver cirrhosis and hepatocellular carcinoma. Research is complicated by a lack of accessible small animal models. The systematic investigation of viruses of small mammals could guide efforts to establish such models, while providing insight into viral evolutionary biology. We have assembled the so-far largest collection of small-mammal samples from around the world, qualified to be screened for bloodborne viruses, including sera and organs from 4,770 rodents (41 species); and sera from 2,939 bats (51 species). Three highly divergent rodent hepacivirus clades were detected in 27 (1.8%) of 1,465 European bank voles ( Myodes glareolus) and 10 (1.9%) of 518 South African four-striped mice ( Rhabdomys pumilio). Bats showed anti-HCV immunoblot reactivities but no virus detection, although the genetic relatedness suggested by the serologic results should have enabled RNA detection using the broadly reactive PCR assays developed for this study. 210 horses and 858 cats and dogs were tested, yielding further horse-associated hepaciviruses but none in dogs or cats. The rodent viruses were equidistant to HCV, exceeding by far the diversity of HCV and the canine/equine hepaciviruses taken together. Five full genomes were sequenced, representing all viral lineages. Salient genome features and distance criteria supported classification of all viruses as hepaciviruses. Quantitative RT-PCR, RNA in-situ hybridisation, and histopathology suggested hepatic tropism with liver inflammation resembling hepatitis C. Recombinant serology for two distinct hepacivirus lineages in 97 bank voles identified seroprevalence rates of 8.3 and 12.4%, respectively. Antibodies in bank vole sera neither cross-reacted with HCV, nor the heterologous bank vole hepacivirus. Co-occurrence of RNA and antibodies was found in 3 of 57 PCR-positive bank vole sera (5.3%). Our data enable new hypotheses regarding HCV evolution and encourage efforts to develop rodent surrogate models for HCV.

          Author Summary

          The hepatitis C virus (HCV) is one of the most relevant causes of liver disease and cancer in humans. The lack of a small animal models represents an important hurdle on our way to understanding, treating, and preventing hepatitis C. The investigation of small mammals could identify virus infections similar to hepatitis C in animals that can be kept in laboratories, such as rodents, and can also yield insights into the evolution of those ancestral virus lineages out of which HCV developed. Here, we investigated a worldwide sample of 4,770 rodents, 2,939 bats, 210 horses and 858 cats and dogs for HCV-related viruses. New viruses were discovered in European bank voles ( Myodes glareolus) and South African four-striped mice ( Rhabdomys pumilio). The disease in bank voles was studied in more detail, suggesting that infection of the liver occurs with similar symptoms to those caused by HCV in humans. These rodents might thus enable the development of new laboratory models of hepatitis C. Moreover, the phylogenetic history of those viruses provides fascinating new ideas regarding the evolution of HCV ancestors.

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          Most cited references 61

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          The delayed rise of present-day mammals.

          Did the end-Cretaceous mass extinction event, by eliminating non-avian dinosaurs and most of the existing fauna, trigger the evolutionary radiation of present-day mammals? Here we construct, date and analyse a species-level phylogeny of nearly all extant Mammalia to bring a new perspective to this question. Our analyses of how extant lineages accumulated through time show that net per-lineage diversification rates barely changed across the Cretaceous/Tertiary boundary. Instead, these rates spiked significantly with the origins of the currently recognized placental superorders and orders approximately 93 million years ago, before falling and remaining low until accelerating again throughout the Eocene and Oligocene epochs. Our results show that the phylogenetic 'fuses' leading to the explosion of extant placental orders are not only very much longer than suspected previously, but also challenge the hypothesis that the end-Cretaceous mass extinction event had a major, direct influence on the diversification of today's mammals.
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            The status of the world's land and marine mammals: diversity, threat, and knowledge.

            Knowledge of mammalian diversity is still surprisingly disparate, both regionally and taxonomically. Here, we present a comprehensive assessment of the conservation status and distribution of the world's mammals. Data, compiled by 1700+ experts, cover all 5487 species, including marine mammals. Global macroecological patterns are very different for land and marine species but suggest common mechanisms driving diversity and endemism across systems. Compared with land species, threat levels are higher among marine mammals, driven by different processes (accidental mortality and pollution, rather than habitat loss), and are spatially distinct (peaking in northern oceans, rather than in Southeast Asia). Marine mammals are also disproportionately poorly known. These data are made freely available to support further scientific developments and conservation action.
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              Liver regeneration.

              Liver regeneration after partial hepatectomy is a very complex and well-orchestrated phenomenon. It is carried out by the participation of all mature liver cell types. The process is associated with signaling cascades involving growth factors, cytokines, matrix remodeling, and several feedbacks of stimulation and inhibition of growth related signals. Liver manages to restore any lost mass and adjust its size to that of the organism, while at the same time providing full support for body homeostasis during the entire regenerative process. In situations when hepatocytes or biliary cells are blocked from regeneration, these cell types can function as facultative stem cells for each other.

                Author and article information

                Role: Editor
                PLoS Pathog
                PLoS Pathog
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                June 2013
                June 2013
                20 June 2013
                : 9
                : 6
                [1 ]Institute of Virology, University of Bonn Medical Centre, Bonn, Germany
                [2 ]Chumakov Institute of Poliomyelitis and Viral Encephalitides, Moscow, Russia
                [3 ]Lomonosov Moscow State University, Moscow, Russia
                [4 ]Architectures et Fonctions des Macromolécules Biologiques, UMR 7257 CNRS and Aix-Marseille University, Marseille, France
                [5 ]Institute of Pathology, University of Cologne Medical Centre, Cologne, Germany
                [6 ]Erasmus MC, Department of Viroscience, Rotterdam, The Netherlands
                [7 ]Institute of Experimental Ecology, University of Ulm, Ulm, Germany
                [8 ]Noctalis, Centre for Bat Protection and Information, Bad Segeberg, Germany
                [9 ]Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Kumasi, Ghana
                [10 ]Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
                [11 ]Centre de Cooperation Internationale de Recherche en Agronomie pour le Développement, UPR AGIRs, Montpellier, France
                [12 ]Department of Infectious Diseases, Molecular Virology, Medical Facility, Heidelberg University, Heidelberg, Germany
                [13 ]Friedrich-Loeffler-Institut, Institute for Virus Diagnostics, Greifswald–Insel Riems, Germany
                [14 ]Friedrich-Loeffler-Institut, Institute for Novel and Emerging Infectious Diseases, Greifswald–Insel Riems, Germany
                [15 ]Institute of Medical Virology (Helmut Ruska Haus), Charité Medical School, Berlin, Germany
                [16 ]Bernhard Nocht Institute for Tropical Medicine, Department of Virology, Hamburg, Germany
                [17 ]Unidad de Investigación Médica en Inmunología, Hospital de Pediatría, México DF, Mexico
                [18 ]Chulalongkorn University, Faculty of Medicine, Neuroscience Center for Research and Development, Bangkok, Thailand
                [19 ]Institute of Virology, Free University of Berlin, Department of Veterinary Medicine, Berlin, Germany
                [20 ]Department of Conservation Ecology and Entomology, Stellenbosch University, Stellenbosch, South Africa
                [21 ]Netherlands Center for Infectious Disease Control, Bilthoven, The Netherlands
                [22 ]Centre International de Recherches Médicales de Franceville, Franceville, Gabon
                [23 ]Institut de Recherche pour le Développement, UMR 224 (MIVEGEC), IRD/CNRS/UM1, Montpellier, France
                Washington University, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: J. Drexler, T. Kuiken, B. Coutard, M. Beer, C. Drosten. Performed the experiments: J. Drexler, V. Corman, D. Ritz, L. Leijten, D. van Riel, B. Coutard, R. Kallies, M. Beer, B. Hoffmann, A. Adam, T. Hemachudha, S. Wacharapluesadee, A. Setién. Analyzed the data: J. Drexler, V. Corman, M. Müeller, C. Drosten, T. Kuiken, A. Lukashev, A. Gmyl, B. Küemmerer. Contributed reagents/materials/analysis tools: B. Coutard, E. Leroy, M. Bourgarel, M. Beer, B. Hoffmann, K. Osterrieder, D. Rupp, R. Bartenschlager, C. Reusken, A. Setién, J. Schmidt-Chanasit, R. Ulrich, D. Krüeger, M. Schlegel, T. Binger, A. Annan, Y. Adu-Sarkodie, S. Oppong, S. Klose, F. Gloza-Rausch, V. Cottontail, T. Hemachudha, S. Wacharapluesadee, S. Matthee. Wrote the paper: J. Drexler, C. Drosten.


                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.

                Page count
                Pages: 17
                This study was funded by the European Union FP7 projects EMPERIE (Grant agreement number 223498), EVA (Grant agreement number 228292) and ANTIGONE (Grant agreement number 278976) and the German Research Foundation (DFG grant DR 772/3-1, KA1241/18-1) to CD; the German Federal Ministry of Education and Research (BMBF) through the National Research Platform for Zoonoses (project code 01KI1018), the Umweltbundesamt (FKZ 370941401), and the Robert Koch-Institut (FKZ 1362/1-924) to RGU; and the Thailand Research Fund (grant RDG5420089) to TH and SW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Evolutionary Biology
                Model Organisms
                Gastroenterology and Hepatology
                Infectious Diseases
                Veterinary Science
                Veterinary Microbiology

                Infectious disease & Microbiology


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