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      Mouse models susceptible to HCoV-229E and HCoV-NL63 and cross protection from challenge with SARS-CoV-2

      research-article
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      Proceedings of the National Academy of Sciences of the United States of America
      National Academy of Sciences
      HCoV-229E, HCoV-NL63, SARS-CoV-2, mouse model, therapeutics, vaccine

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          Significance

          Human coronavirus 229E(HCoV-229E) and NL63 (HCoV-NL63) are endemic worldwide and cause mild upper respiratory infections or occasionally, more severe lower respiratory tract infections. Mice are not permissive to these virus infections primarily because they lack receptors for these viruses. The recent emergence of COVID-19 emphasizes the need to develop animal models for these CoVs. Here, we generated mouse models for 229E and NL63 by exogenous delivery of their receptors, hAPN and hACE2, respectively, using adenoviruses. We show that these mouse models are useful for analyzing immune responses and for evaluating vaccines and potential therapeutic drugs against HCoV-229E and HCoV-NL63. Moreover, CCCoV-infected mice were partially protected from SARS-CoV-2 infection.

          Abstract

          Human coronavirus 229E (HCoV-229E) and NL63 (HCoV-NL63) are endemic causes of upper respiratory infections such as the “common cold” but may occasionally cause severe lower respiratory tract disease in the elderly and immunocompromised patients. There are no approved antiviral drugs or vaccines for these common cold coronaviruses (CCCoV). The recent emergence of COVID-19 and the possible cross-reactive antibody and T cell responses between these CCCoV and SARS-CoV-2 emphasize the need to develop experimental animal models for CCCoV. Mice are an ideal experimental animal model for such studies, but are resistant to HCoV-229E and HCoV-NL63 infections. Here, we generated 229E and NL63 mouse models by exogenous delivery of their receptors, human hAPN and hACE2 using replication-deficient adenoviruses (Ad5-hAPN and Ad5-hACE2), respectively. Ad5-hAPN- and Ad5-hACE2-sensitized IFNAR −/− and STAT1 −/− mice developed pneumonia characterized by inflammatory cell infiltration with virus clearance occurring 7 d post infection. Ad5-hAPN- and Ad5-hACE2-sensitized mice generated virus-specific T cells and neutralizing antibodies after 229E or NL63 infection, respectively. Remdesivir and a vaccine candidate targeting spike protein of 229E and NL63 accelerated viral clearance of virus in these mice. 229E- and NL63-infected mice were partially protected from SARS-CoV-2 infection, likely mediated by cross-reactive T cell responses. Ad5-hAPN- and Ad5-hACE2-transduced mice are useful for studying pathogenesis and immune responses induced by HCoV-229E and HCoV-NL63 infections and for validation of broadly protective vaccines, antibodies, and therapeutics against human respiratory coronaviruses including SARS-CoV-2.

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          Most cited references53

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          A pneumonia outbreak associated with a new coronavirus of probable bat origin

          Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
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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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              Remdesivir for the Treatment of Covid-19 — Final Report

              Abstract Background Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious. Methods We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. Results A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%). Conclusions Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.)
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                Author and article information

                Contributors
                Journal
                Proc Natl Acad Sci U S A
                Proc Natl Acad Sci U S A
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                18 January 2023
                24 January 2023
                18 January 2023
                : 120
                : 4
                : e2202820120
                Affiliations
                [1] aState Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou 510182, China
                [2] bThe Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong , Hong Kong SAR, PR China
                [3] cLi Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Hong Kong SAR, PR China
                [4] dGuangzhou Customs District Technology Center , Guangzhou 510700, China
                [5] ePediatric Pulmonary Department, Guangzhou Women and Children's Medical Center, Guangzhou Medical University , Guangzhou 510623, China
                [6] fNHC Key laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100176, China
                [7] gKey Laboratory of Biosafety, National Health and Family Planning Commission, National Institute for Viral Disease Control and Prevention, Chinese center for disease control and prevention , Beijing 102206, China
                [8] hHong Kong University – Pasteur Research Pole , Hong Kong Special Administrative Region, China
                [9] iSchool of Public Health, The University of Hong Kong , Hong Kong Special Administrative Region, China
                [10] jInstitute of Infectious Disease, Guangzhou Eighth People's Hospital of Guangzhou Medical University , Guangzhou 510060, China
                [11] kGuangzhou Laboratory , Bio-Island, Guangzhou 510320, China
                [12] lShanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University , Shanghai 201210, China
                [13] mNational Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen 518112, China
                Author notes
                2To whom correspondence may be addressed. Email: zhaojingxian@ 123456gird.cn , malik@ 123456hku.hk , or zhaojincun@ 123456gird.cn .

                Contributed by Malik Peiris; received February 18, 2022; accepted October 24, 2022; reviewed by Ralph Baric, Luis Enjuanes and Emmie de Wit

                1D.L., C.C., D.C., A.Z., F.L., Z.Z., C.K.P.M., J.D., X.L., and Y.J. contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-5963-1136
                https://orcid.org/0000-0001-8217-5995
                Article
                202202820
                10.1073/pnas.2202820120
                9942917
                36652473
                6b34ccc9-7a2f-4f6d-b26e-9e009a7a8226
                Copyright © 2023 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

                History
                : 18 February 2022
                : 24 October 2022
                Page count
                Pages: 12, Words: 7729
                Funding
                Funded by: National Natural Science Foundation of China (NSFC), FundRef 501100001809;
                Award ID: 81861168032
                Award ID: 82100117
                Award ID: 82025001
                Award ID: 82025001
                Award ID: 8181101118
                Award ID: 91842106
                Award Recipient : Jincun Zhao
                Funded by: Ministries of Science and Technology, Education of Guangdong province, FundRef ;
                Award ID: 2020B1111330001
                Award ID: 2020A111128008
                Award ID: 2020B1111320003
                Award ID: 2020KZDZX1158
                Award ID: B195001248
                Award Recipient : Donglan Liu Award Recipient : Yingkang Jin Award Recipient : Malik Peiris Award Recipient : Jincun Zhao
                Funded by: ZHONGNANSHAN MEDICAL FOUNDATION OF GUANGDONG PROVINCE, FundRef ;
                Award ID: ZNSA-2020013
                Award Recipient : Donglan Liu Award Recipient : Yingkang Jin Award Recipient : Malik Peiris Award Recipient : Jincun Zhao
                Funded by: State Key Laboratory of Respiratory Disease, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease, FundRef ;
                Award ID: GHMJLRID-Z-202101
                Award Recipient : Donglan Liu Award Recipient : Yingkang Jin Award Recipient : Malik Peiris Award Recipient : Jincun Zhao
                Funded by: National Key R&D Program of China, FundRef ;
                Award ID: 2021YFC2301700
                Award Recipient : Donglan Liu Award Recipient : Yingkang Jin Award Recipient : Malik Peiris Award Recipient : Jincun Zhao
                Funded by: Guangzhou Institute of Respiratory Health Open Project, FundRef ;
                Award ID: 2020GIRHHMS24
                Award Recipient : Donglan Liu Award Recipient : Yingkang Jin Award Recipient : Malik Peiris Award Recipient : Jincun Zhao
                Funded by: Guangdong Natural Science Foundation General Program, FundRef ;
                Award ID: 2018A030313965
                Award Recipient : Donglan Liu Award Recipient : Yingkang Jin Award Recipient : Malik Peiris Award Recipient : Jincun Zhao
                Funded by: PhD Startup Foundation from Guangzhou Women and Children’s Medical Center, FundRef ;
                Award ID: 2018-2020
                Award Recipient : Donglan Liu Award Recipient : Yingkang Jin Award Recipient : Malik Peiris Award Recipient : Jincun Zhao
                Funded by: Guangzhou Science and Technology Planning Program Minicipal School/Institute-Joint Funded Program, FundRef ;
                Award ID: 202102010143
                Award Recipient : Donglan Liu Award Recipient : Yingkang Jin Award Recipient : Malik Peiris Award Recipient : Jincun Zhao
                Funded by: Guangdong Medical Technology Research Foundation, FundRef ;
                Award ID: B2022233
                Award Recipient : Donglan Liu Award Recipient : Yingkang Jin Award Recipient : Malik Peiris Award Recipient : Jincun Zhao
                Categories
                research-article, Research Article
                covid-19, Coronavirus (COVID-19)
                microbio, Microbiology
                423
                530
                Biological Sciences
                Microbiology
                Custom metadata
                free

                hcov-229e,hcov-nl63,sars-cov-2,mouse model,therapeutics,vaccine
                hcov-229e, hcov-nl63, sars-cov-2, mouse model, therapeutics, vaccine

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