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      Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

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          Abstract

          Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells 1, 2 . Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2) 3, 4 , isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein. We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells. 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein. Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells. Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells. Together our data indicate that ACE2 is a functional receptor for SARS-CoV.

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          The online version of this article (doi:10.1038/nature02145) contains supplementary material, which is available to authorized users.

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

          Christian Drosten, Stephan Günther, Wolfgang Preiser … (2003)
          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.

            Thomas G Ksiazek, Dean Erdman, Cynthia Goldsmith … (2003)
            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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              Characterization of a novel coronavirus associated with severe acute respiratory syndrome.

              P Rota (2003)
              In March 2003, a novel coronavirus (SARS-CoV) was discovered in association with cases of severe acute respiratory syndrome (SARS). The sequence of the complete genome of SARS-CoV was determined, and the initial characterization of the viral genome is presented in this report. The genome of SARS-CoV is 29,727 nucleotides in length and has 11 open reading frames, and its genome organization is similar to that of other coronaviruses. Phylogenetic analyses and sequence comparisons showed that SARS-CoV is not closely related to any of the previously characterized coronaviruses.
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                Author and article information

                Contributors
                Hyeryun Choe: hyeryun.choe@tch.harvard.edu
                Michael Farzan: farzan@mbcrr.harvard.edu
                Journal
                Journal ID (nlm-ta): Nature
                Journal ID (iso-abbrev): Nature
                Title: Nature
                Publisher: Nature Publishing Group UK (London )
                ISSN (Print): 0028-0836
                ISSN (Electronic): 1476-4687
                Publication date (Print): 2003
                Volume: 426
                Issue: 6965
                Pages: 450-454
                Affiliations
                [1 ]Department of Medicine (Microbiology and Molecular Genetics), Partners AIDS Research Center, Brigham and Women's Hospital, ,
                [2 ]Perlmutter Laboratory, Pulmonary Division, Children's Hospital, Department of Pediatrics, ,
                [3 ]GRID grid.38142.3c, ISNI 000000041936754X, Dana-Farber Cancer Institute, Department of Medicine, , Harvard Medical School, ; Massachusetts 02115 Boston, USA
                [4 ]GRID grid.429997.8, ISNI 0000 0004 1936 7531, Tufts University Core Facility, Tufts University School of Medicine, ; Massachusetts 02111 Boston, USA
                [5 ]GRID grid.168645.8, ISNI 0000 0001 0742 0364, Program in Molecular Medicine, , University of Massachusetts Medical School, ; Massachusetts 01605 Worcester, USA
                Article
                Publisher ID: BFnature02145
                DOI: 10.1038/nature02145
                PMC ID: 7095016
                PubMed ID: 14647384
                SO-VID: b54e3f1e-9858-4e1c-951a-2ae8af0d3111
                Copyright © © Macmillan Magazines Ltd. 2003
                License:

                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.

                History
                Date received : 14 September 2003
                Date accepted : 23 October 2003
                Categories
                Subject: Article
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                issue-copyright-statement © Springer Nature Limited 2003

                ScienceOpen disciplines: Uncategorized
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