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      A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury

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          Abstract

          During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world 1, 2, 3 . A new coronavirus (SARS-CoV) was identified as the SARS pathogen 4, 5, 6, 7 , which triggered severe pneumonia and acute, often lethal, lung failure 8 . Moreover, among infected individuals influenza such as the Spanish flu 9, 10 and the emergence of new respiratory disease viruses 11, 12 have caused high lethality resulting from acute lung failure 13 . In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor 14 . The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses.

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          The online version of this article (doi:10.1038/nm1267) contains supplementary material, which is available to authorized users.

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          Most cited references15

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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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              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
                jiang@pumc.edu.cn
                Journal
                Nat Med
                Nat. Med
                Nature Medicine
                Nature Publishing Group US (New York )
                1078-8956
                1546-170X
                10 July 2005
                2005
                : 11
                : 8
                : 875-879
                Affiliations
                [1 ]GRID grid.417521.4, ISNI 0000 0001 0008 2788, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr-gasse 7, ; Vienna, A-1030 Austria
                [2 ]National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 5 Dongdan Santiao, Beijing, 100005 China
                [3 ]GRID grid.413106.1, ISNI 0000 0000 9889 6335, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 5 Dongdan Santiao, ; Beijing, 100005 China
                [4 ]GRID grid.413106.1, ISNI 0000 0000 9889 6335, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 5 Dongdan Santiao, ; Beijing, 100005 China
                [5 ]GRID grid.241167.7, ISNI 0000 0001 2185 3318, The Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Gray Building, ; G054 Medical Center Boulevard, Winston-Salem, 27157-1032 North Carolina USA
                [6 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Department of Medicine and Interdepartmental Division of Critical Care, , University of Toronto; St. Michael's Hospital, ; 30 Bond Street, Toronto, M5B 1W8 Canada
                Article
                BFnm1267
                10.1038/nm1267
                7095783
                16007097
                7826d3c9-4a18-4c22-8beb-b8b077aa21ac
                © Nature Publishing Group 2005

                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
                : 22 April 2005
                : 3 June 2005
                Categories
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                Custom metadata
                © The Author(s), under exclusive licence to Springer Nature America, Inc. 2005

                Medicine
                Medicine

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