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      Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC

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          Abstract

          Human coronavirus-EMC (hCoV-EMC) is a new coronavirus that has killed around half of the few humans infected so far; this study now identifies DPP4 as the receptor that this virus uses to infect cells.

          Supplementary information

          The online version of this article (doi:10.1038/nature12005) contains supplementary material, which is available to authorized users.

          Human receptor for emerging coronavirus

          The emerging pathogenic coronavirus hCoV-EMC, first identified in September 2012, has been fatal in about half of the few humans infected so far. Bart Haagmans and colleagues have now identified the receptor that this virus uses to infect cells. In contrast to the related virus SARS-CoV, which uses angiotensin converting enzyme 2, the functional receptor for hCoV-EMC is dipeptidyl peptidase 4 (DPP4, also known as CD26), an exopeptidase found on non-ciliated cells in the lower respiratory tract. This enzyme is highly conserved across different species, and hCoV-EMC can also use bat DPP4 as a functional receptor — a possible clue as to the host range and epidemiological history of this new virus. The findings may also be important for the development of intervention strategies.

          Supplementary information

          The online version of this article (doi:10.1038/nature12005) contains supplementary material, which is available to authorized users.

          Abstract

          Most human coronaviruses cause mild upper respiratory tract disease but may be associated with more severe pulmonary disease in immunocompromised individuals 1 . However, SARS coronavirus caused severe lower respiratory disease with nearly 10% mortality and evidence of systemic spread 2 . Recently, another coronavirus (human coronavirus-Erasmus Medical Center (hCoV-EMC)) was identified in patients with severe and sometimes lethal lower respiratory tract infection 3, 4 . Viral genome analysis revealed close relatedness to coronaviruses found in bats 5 . Here we identify dipeptidyl peptidase 4 (DPP4; also known as CD26) as a functional receptor for hCoV-EMC. DPP4 specifically co-purified with the receptor-binding S1 domain of the hCoV-EMC spike protein from lysates of susceptible Huh-7 cells. Antibodies directed against DPP4 inhibited hCoV-EMC infection of primary human bronchial epithelial cells and Huh-7 cells. Expression of human and bat ( Pipistrellus pipistrellus) DPP4 in non-susceptible COS-7 cells enabled infection by hCoV-EMC. The use of the evolutionarily conserved DPP4 protein from different species as a functional receptor provides clues about the host range potential of hCoV-EMC. In addition, it will contribute critically to our understanding of the pathogenesis and epidemiology of this emerging human coronavirus, and may facilitate the development of intervention strategies.

          Supplementary information

          The online version of this article (doi:10.1038/nature12005) contains supplementary material, which is available to authorized users.

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          Most cited references 25

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

            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. Supplementary information The online version of this article (doi:10.1038/nature02145) contains supplementary material, which is available to authorized users.
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              Bats are natural reservoirs of SARS-like coronaviruses.

              Severe acute respiratory syndrome (SARS) emerged in 2002 to 2003 in southern China. The origin of its etiological agent, the SARS coronavirus (SARS-CoV), remains elusive. Here we report that species of bats are a natural host of coronaviruses closely related to those responsible for the SARS outbreak. These viruses, termed SARS-like coronaviruses (SL-CoVs), display greater genetic variation than SARS-CoV isolated from humans or from civets. The human and civet isolates of SARS-CoV nestle phylogenetically within the spectrum of SL-CoVs, indicating that the virus responsible for the SARS outbreak was a member of this coronavirus group.
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                Author and article information

                Contributors
                b.j.bosch@uu.nl
                b.haagmans@erasmusmc.nl
                Journal
                Nature
                Nature
                Nature
                Nature Publishing Group UK (London )
                0028-0836
                1476-4687
                13 March 2013
                2013
                : 495
                : 7440
                : 251-254
                Affiliations
                [1 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Viroscience, , Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands, ; ,
                [2 ]GRID grid.5477.1, ISNI 0000000120346234, Virology Division, Department of Infectious Diseases & Immunology, , Faculty of Veterinary Medicine, Utrecht University, 3508 TD Utrecht, the Netherlands, ; ,
                [3 ]Viroclinics Biosciences BV, 3029 AK Rotterdam, The Netherlands, ,
                [4 ]GRID grid.5645.2, ISNI 000000040459992X, Proteomics Department, , Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands, ; ,
                [5 ]GRID grid.15090.3d, ISNI 0000 0000 8786 803X, Institute of Virology, University of Bonn Medical Centre, 53105 Bonn, Germany, ; ,
                [6 ]GRID grid.413349.8, ISNI 0000 0001 2294 4705, Institute of Immunobiology, Kantonal Hospital St Gallen, 9007 St Gallen, Switzerland, ; ,
                [7 ]GRID grid.416111.2, ISNI 0000 0004 1790 6466, Virology Laboratory, Dr Soliman Fakeeh Hospital, ; Jeddah, Saudi Arabia
                [8 ]GRID grid.7400.3, ISNI 0000 0004 1937 0650, Vetsuisse Faculty, University of Zürich, 8057 Zürich, Switzerland, ; ,
                Article
                BFnature12005
                10.1038/nature12005
                7095326
                23486063
                © 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

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                viral pathogenesis

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