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      Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling

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          Abstract

          Israelow et al. show that AAV-mediated expression of human ACE2 allows for SARS-CoV-2 infection and disease investigation in mice. This pathology is in part driven by type I interferon signaling, which recruits inflammatory immune cells without aborting viral replication.

          Abstract

          Severe acute respiratory syndrome–coronavirus 2 (SARS-Cov-2) has caused over 13,000,000 cases of coronavirus disease (COVID-19) with a significant fatality rate. Laboratory mice have been the stalwart of therapeutic and vaccine development; however, they do not support infection by SARS-CoV-2 due to the virus’s inability to use the mouse orthologue of its human entry receptor angiotensin-converting enzyme 2 (hACE2). While hACE2 transgenic mice support infection and pathogenesis, these mice are currently limited in availability and are restricted to a single genetic background. Here we report the development of a mouse model of SARS-CoV-2 based on adeno-associated virus (AAV)–mediated expression of hACE2. These mice support viral replication and exhibit pathological findings found in COVID-19 patients. Moreover, we show that type I interferons do not control SARS-CoV-2 replication in vivo but are significant drivers of pathological responses. Thus, the AAV-hACE2 mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patient-derived virus in mice of diverse genetic backgrounds.

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          A Novel Coronavirus from Patients with Pneumonia in China, 2019

          Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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            Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China

            In December 2019, novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited.
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              SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

              Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - review & editing
                Role: Formal analysisRole: Investigation
                Role: InvestigationRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - review & editing
                Role: Data curationRole: Writing - review & editing
                Role: Data curationRole: Formal analysis
                Role: Investigation
                Role: Resources
                Role: Resources
                Role: Investigation
                Role: Funding acquisitionRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing - review & editing
                Role: Funding acquisitionRole: ResourcesRole: SupervisionRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing - review & editing
                Journal
                J Exp Med
                J. Exp. Med
                jem
                The Journal of Experimental Medicine
                Rockefeller University Press
                0022-1007
                1540-9538
                07 December 2020
                04 August 2020
                04 August 2020
                : 217
                : 12
                : e20201241
                Affiliations
                [1 ]Department of Immunobiology, Yale University School of Medicine, New Haven, CT
                [2 ]Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT
                [3 ]Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT
                [4 ]Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT
                [5 ]Department of Pathology, Yale University School of Medicine, New Haven, CT
                [6 ]Howard Hughes Medical Institute, Chevy Chase, MD
                Author notes
                Correspondence to Akiko Iwasaki: akiko.iwasaki@ 123456yale.edu

                Disclosures: A. Ring reported a patent to novel binding partner that interacts with SARS-CoV2 spike N-terminal domain pending; reports, "Unrelated to the subject of the work, I have founded, co-founded, and/or hold equity in biotechnology companies including Simcha Therapeutics, Forty Seven Inc., and ALX Oncology. I have also consulted for Medicenna Therapeutics, a company that licensed patents I invented in immuno-oncology. None of these companies are in the SARS-CoV-2 space or work on infectious disease to my knowledge. Broadly related to the subject of this work, within the past year, I have purchased and disposed shares in Gilead Sciences and Vir Biotechnology, which are working on therapeutics in the coronavirus space. I currently hold no shares in either of those companies." No other disclosures were reported.

                [*]

                B. Israelow and E. Song contributed equally to this paper.

                Author information
                https://orcid.org/0000-0002-1308-8246
                https://orcid.org/0000-0001-5448-5865
                https://orcid.org/0000-0001-9251-8592
                https://orcid.org/0000-0001-6118-872X
                https://orcid.org/0000-0001-9635-1021
                https://orcid.org/0000-0003-2663-6544
                https://orcid.org/0000-0002-6402-2730
                https://orcid.org/0000-0002-2832-1610
                https://orcid.org/0000-0002-9447-0868
                https://orcid.org/0000-0002-2055-5885
                https://orcid.org/0000-0003-3699-2446
                https://orcid.org/0000-0003-2495-9403
                https://orcid.org/0000-0002-7824-9856
                Article
                jem.20201241
                10.1084/jem.20201241
                7401025
                32750141
                d382321a-cf7f-4b54-a160-8beccbbdedf8
                © 2020 Israelow et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 15 June 2020
                : 15 July 2020
                : 23 July 2020
                Page count
                Pages: 10
                Funding
                Funded by: National Institutes of Health, DOI http://dx.doi.org/10.13039/100000002;
                Award ID: 2T32AI007517-16
                Award ID: T32GM007205
                Award ID: F30CA239444
                Award ID: R37AI041699
                Award ID: AI054359
                Award ID: AI127429
                Award ID: T32AI007019
                Award ID: K08 AI128043
                Funded by: Women’s Health Research at Yale;
                Funded by: Mercatus Center;
                Funded by: G. Harold and Leila Y. Mathers Foundation, DOI http://dx.doi.org/10.13039/100011671;
                Funded by: Ludwig Family Foundation;
                Funded by: Howard Hughes Medical Institute, DOI http://dx.doi.org/10.13039/100000011;
                Categories
                Article
                Innate Immunity and Inflammation
                Infectious Disease and Host Defense

                Medicine
                Medicine

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