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      A decade after SARS: strategies for controlling emerging coronaviruses

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          Key Points

          • Two highly pathogenic human coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), have emerged in the past decade. The lack of any clinically approved antiviral treatments or vaccines for either virus emphasizes the importance of the design of effective therapeutics and preventives.

          • Bats have been implicated as reservoirs of both SARS-CoV and MERS-CoV as well as related viruses and other human coronaviruses (HCoVs), such as HCoV-229E and HCoV-NL63. The dispersion of bat species over much of the globe probably enhances their potential to act as reservoirs for pathogens, some of which are extremely virulent and potentially lethal to other animals and humans.

          • Multiple animal models for SARS-CoV infection exist, although mouse models have been the most thoroughly characterized. Mouse-adapted SARS-CoV is capable of causing pathology that is representative of human infections in both young and aged animals.

          • Small animal models for MERS-CoV infection have not yet been reported, although the possibility of further ongoing selection in the receptor-binding sequence in the spike protein or other sequences that are important for host specificity might contribute to this limitation. A mild disease phenotype that can include either localized or widespread pneumonia is observed in inoculated macaques.

          • Multiple vaccine strategies have been attempted with coronaviruses, mostly (but not exclusively) targeting the spike glycoprotein. Successful live-attenuated vaccines have utilized reverse genetic strategies to delete the envelope protein or inactivate the exonuclease activity of non-structural protein 14 (nsp14) .

          • MERS-CoV, similarly to SARS-CoV in 2003, has the potential to have a profound impact on the human population; however, its low penetrance thus far suggests that the virus might either ultimately fail to develop a niche in humans or it might still be adapting to human hosts and that the worst of its effects are yet to come.

          • Coronavirus phylogeny shows an incredible diversity in antigenic variants, which leads to limited cross-protection against infection with different strains, even within a phylogenetic subcluster. Consequently, the risk of introducing novel coronaviruses into naive human and animal populations remains high.

          Supplementary information

          The online version of this article (doi:10.1038/nrmicro3143) contains supplementary material, which is available to authorized users.

          Abstract

          The emergence of severe acute respiratory syndrome (SARS) coronavirus and, more recently, Middle East respiratory syndrome (MERS) coronavirus has highlighted the pathogenic and epidemic potential of this virus family. Here, Graham, Donaldson and Baric review key biological properties of coronaviruses and how to target them with potential therapeutics.

          Supplementary information

          The online version of this article (doi:10.1038/nrmicro3143) contains supplementary material, which is available to authorized users.

          Abstract

          Two novel coronaviruses have emerged in humans in the twenty-first century: severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), both of which cause acute respiratory distress syndrome (ARDS) and are associated with high mortality rates. There are no clinically approved vaccines or antiviral drugs available for either of these infections; thus, the development of effective therapeutic and preventive strategies that can be readily applied to new emergent strains is a research priority. In this Review, we describe the emergence and identification of novel human coronaviruses over the past 10 years, discuss their key biological features, including tropism and receptor use, and summarize approaches for developing broadly effective vaccines.

          Supplementary information

          The online version of this article (doi:10.1038/nrmicro3143) contains supplementary material, which is available to authorized users.

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          Most cited references77

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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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            Identification of a Novel Coronavirus in Patients with Severe Acute Respiratory Syndrome

            The severe acute respiratory syndrome (SARS) has recently been identified as a new clinical entity. SARS is thought to be caused by an unknown infectious agent. Clinical specimens from patients with SARS were searched for unknown viruses with the use of cell cultures and molecular techniques. A novel coronavirus was identified in patients with SARS. The virus was isolated in cell culture, and a sequence 300 nucleotides in length was obtained by a polymerase-chain-reaction (PCR)-based random-amplification procedure. Genetic characterization indicated that the virus is only distantly related to known coronaviruses (identical in 50 to 60 percent of the nucleotide sequence). On the basis of the obtained sequence, conventional and real-time PCR assays for specific and sensitive detection of the novel virus were established. Virus was detected in a variety of clinical specimens from patients with SARS but not in controls. High concentrations of viral RNA of up to 100 million molecules per milliliter were found in sputum. Viral RNA was also detected at extremely low concentrations in plasma during the acute phase and in feces during the late convalescent phase. Infected patients showed seroconversion on the Vero cells in which the virus was isolated. The novel coronavirus might have a role in causing SARS. Copyright 2003 Massachusetts Medical Society
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              A novel coronavirus associated with severe acute respiratory syndrome.

              A worldwide outbreak of severe acute respiratory syndrome (SARS) has been associated with exposures originating from a single ill health care worker from Guangdong Province, China. We conducted studies to identify the etiologic agent of this outbreak. We received clinical specimens from patients in seven countries and tested them, using virus-isolation techniques, electron-microscopical and histologic studies, and molecular and serologic assays, in an attempt to identify a wide range of potential pathogens. None of the previously described respiratory pathogens were consistently identified. However, a novel coronavirus was isolated from patients who met the case definition of SARS. Cytopathological features were noted in Vero E6 cells inoculated with a throat-swab specimen. Electron-microscopical examination revealed ultrastructural features characteristic of coronaviruses. Immunohistochemical and immunofluorescence staining revealed reactivity with group I coronavirus polyclonal antibodies. Consensus coronavirus primers designed to amplify a fragment of the polymerase gene by reverse transcription-polymerase chain reaction (RT-PCR) were used to obtain a sequence that clearly identified the isolate as a unique coronavirus only distantly related to previously sequenced coronaviruses. With specific diagnostic RT-PCR primers we identified several identical nucleotide sequences in 12 patients from several locations, a finding consistent with a point-source outbreak. Indirect fluorescence antibody tests and enzyme-linked immunosorbent assays made with the new isolate have been used to demonstrate a virus-specific serologic response. This virus may never before have circulated in the U.S. population. A novel coronavirus is associated with this outbreak, and the evidence indicates that this virus has an etiologic role in SARS. Because of the death of Dr. Carlo Urbani, we propose that our first isolate be named the Urbani strain of SARS-associated coronavirus. Copyright 2003 Massachusetts Medical Society
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                Author and article information

                Contributors
                rbaric@email.unc.edu
                Journal
                Nat Rev Microbiol
                Nat. Rev. Microbiol
                Nature Reviews. Microbiology
                Nature Publishing Group UK (London )
                1740-1526
                1740-1534
                11 November 2013
                2013
                : 11
                : 12
                : 836-848
                Affiliations
                [1 ]GRID grid.10698.36, ISNI 0000000122483208, Department of Epidemiology, , University of North Carolina at Chapel Hill, ; Chapel Hill, 27599 North Carolina USA
                [2 ]GRID grid.10698.36, ISNI 0000000122483208, Department of Microbiology and Immunology, , University of North Carolina at Chapel Hill, ; Chapel Hill, 27599 North Carolina USA
                Article
                BFnrmicro3143
                10.1038/nrmicro3143
                5147543
                24217413
                d1566555-f2f6-4469-ae79-367e8aa51cda
                © Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2013

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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                © Springer Nature Limited 2013

                sars virus,pathogens,viral infection,viral epidemiology,vaccines

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