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      Infection with MERS-CoV Causes Lethal Pneumonia in the Common Marmoset

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          Abstract

          The availability of a robust disease model is essential for the development of countermeasures for Middle East respiratory syndrome coronavirus (MERS-CoV). While a rhesus macaque model of MERS-CoV has been established, the lack of uniform, severe disease in this model complicates the analysis of countermeasure studies. Modeling of the interaction between the MERS-CoV spike glycoprotein and its receptor dipeptidyl peptidase 4 predicted comparable interaction energies in common marmosets and humans. The suitability of the marmoset as a MERS-CoV model was tested by inoculation via combined intratracheal, intranasal, oral and ocular routes. Most of the marmosets developed a progressive severe pneumonia leading to euthanasia of some animals. Extensive lesions were evident in the lungs of all animals necropsied at different time points post inoculation. Some animals were also viremic; high viral loads were detected in the lungs of all infected animals, and total RNAseq demonstrated the induction of immune and inflammatory pathways. This is the first description of a severe, partially lethal, disease model of MERS-CoV, and as such will have a major impact on the ability to assess the efficacy of vaccines and treatment strategies as well as allowing more detailed pathogenesis studies.

          Author Summary

          The development of vaccines and treatment strategies is aided by robust animal disease models that accurately depict the illness that is observed in humans. Here we describe a new, improved model for MERS-CoV using the common marmoset, whereby the severe, and even lethal, illness that has been observed in many human cases is recapitulated. Prior to the development of this model, the only available animal models for MERS-CoV infection were the rhesus macaque and a mouse model that requires adenovirus-transduced expression of the human version of the protein required for virus entry. The rhesus macaque model more closely mimics the mild to moderate disease observed in some patients—mainly those without significant comorbidities. The increased severity of illness in the common marmoset model is an important advance in the ability to evaluate potential therapeutic agents against MERS-CoV, as discrimination between successfully treated and control animals should be more apparent. In addition, the closer models recapitulate the disease observed in humans, the more likely findings can be eventually translated into use in humans.

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          Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.

          A previously unknown coronavirus was isolated from the sputum of a 60-year-old man who presented with acute pneumonia and subsequent renal failure with a fatal outcome in Saudi Arabia. The virus (called HCoV-EMC) replicated readily in cell culture, producing cytopathic effects of rounding, detachment, and syncytium formation. The virus represents a novel betacoronavirus species. The closest known relatives are bat coronaviruses HKU4 and HKU5. Here, the clinical data, virus isolation, and molecular identification are presented. The clinical picture was remarkably similar to that of the severe acute respiratory syndrome (SARS) outbreak in 2003 and reminds us that animal coronaviruses can cause severe disease in humans.
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            Distance-scaled, finite ideal-gas reference state improves structure-derived potentials of mean force for structure selection and stability prediction.

            The distance-dependent structure-derived potentials developed so far all employed a reference state that can be characterized as a residue (atom)-averaged state. Here, we establish a new reference state called the distance-scaled, finite ideal-gas reference (DFIRE) state. The reference state is used to construct a residue-specific all-atom potential of mean force from a database of 1011 nonhomologous (less than 30% homology) protein structures with resolution less than 2 A. The new all-atom potential recognizes more native proteins from 32 multiple decoy sets, and raises an average Z-score by 1.4 units more than two previously developed, residue-specific, all-atom knowledge-based potentials. When only backbone and C(beta) atoms are used in scoring, the performance of the DFIRE-based potential, although is worse than that of the all-atom version, is comparable to those of the previously developed potentials on the all-atom level. In addition, the DFIRE-based all-atom potential provides the most accurate prediction of the stabilities of 895 mutants among three knowledge-based all-atom potentials. Comparison with several physical-based potentials is made.
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              Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques.

              In 2012, a novel betacoronavirus, designated Middle East respiratory syndrome coronavirus or MERS-CoV and associated with severe respiratory disease in humans, emerged in the Arabian Peninsula. To date, 108 human cases have been reported, including cases of human-to-human transmission. The availability of an animal disease model is essential for understanding pathogenesis and developing effective countermeasures. Upon a combination of intratracheal, ocular, oral, and intranasal inoculation with 7 × 10(6) 50% tissue culture infectious dose of the MERS-CoV isolate HCoV-EMC/2012, rhesus macaques developed a transient lower respiratory tract infection. Clinical signs, virus shedding, virus replication in respiratory tissues, gene expression, and cytokine and chemokine profiles peaked early in infection and decreased over time. MERS-CoV caused a multifocal, mild to marked interstitial pneumonia, with virus replication occurring mainly in alveolar pneumocytes. This tropism of MERS-CoV for the lower respiratory tract may explain the severity of the disease observed in humans and the, up to now, limited human-to-human transmission.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                August 2014
                21 August 2014
                : 10
                : 8
                : e1004250
                Affiliations
                [1 ]Disease Modeling and Transmission, Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, United States of America
                [2 ]Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, United States of America
                [3 ]Department of Microbiology, University of Washington, Seattle, Washington, United States of America
                [4 ]Virus Ecology Unit, Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, United States of America
                [5 ]Department of Immunology and Microbial Science, Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America
                [6 ]Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America
                [7 ]Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada
                Vanderbilt University, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: DF EdW HF VJM. Performed the experiments: DF EdW FF NvD EH LN RL TL JZ JSM DPS HF VJM. Analyzed the data: DF EdW ALR AO XP MJT DPS MGK HF VJM. Wrote the paper: DF EdW ALR HF VJM.

                Article
                PPATHOGENS-D-14-00320
                10.1371/journal.ppat.1004250
                4140844
                25144235
                3943c7bd-2205-4a23-b3c7-80e58d9f9b96
                Copyright @ 2014

                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 5 February 2014
                : 30 June 2014
                Page count
                Pages: 13
                Funding
                This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) in addition to grants for the Development of Nonhuman Primate Reference Transcriptome Resources (R24OD011172-03) and the Washington National Primate Research Center (P51OD010425) to MGK. 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
                Microbiology
                Virology
                Emerging Viral Diseases
                Animal Models of Infection
                Organisms
                Animals
                Vertebrates
                Mammals
                Primates
                Monkeys
                New World monkeys
                Marmosets
                Research and Analysis Methods
                Model Organisms
                Animal Models

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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