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      Spike mutation D614G alters SARS-CoV-2 fitness and neutralization susceptibility

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          Abstract

          A spike protein mutation D614G became dominant in SARS-CoV-2 during the COVID-19 pandemic. However, the mutational impact on viral spread and vaccine efficacy remains to be defined. Here we engineer the D614G mutation in the SARS-CoV-2 USA-WA1/2020 strain and characterize its effect on viral replication, pathogenesis, and antibody neutralization. The D614G mutation significantly enhances SARS-CoV-2 replication on human lung epithelial cells and primary human airway tissues, through an improved infectivity of virions with the spike receptor-binding domain in an “up” conformation for binding to ACE2 receptor. Hamsters infected with D614 or G614 variants developed similar levels of weight loss. However, the G614 virus produced higher infectious titers in the nasal washes and trachea, but not lungs, than the D614 virus. The hamster results confirm clinical evidence that the D614G mutation enhances viral loads in the upper respiratory tract of COVID-19 patients and may increases transmission. For antibody neutralization, sera from D614 virus-infected hamsters consistently exhibit higher neutralization titers against G614 virus than those against D614 virus, indicating that (i) the mutation may not reduce the ability of vaccines in clinical trials to protect against COVID-19 and (ii) therapeutic antibodies should be tested against the circulating G614 virus before clinical development.

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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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              Virological assessment of hospitalized patients with COVID-2019

              Coronavirus disease 2019 (COVID-19) is an acute infection of the respiratory tract that emerged in late 20191,2. Initial outbreaks in China involved 13.8% of cases with severe courses, and 6.1% of cases with critical courses3. This severe presentation may result from the virus using a virus receptor that is expressed predominantly in the lung2,4; the same receptor tropism is thought to have determined the pathogenicity-but also aided in the control-of severe acute respiratory syndrome (SARS) in 20035. However, there are reports of cases of COVID-19 in which the patient shows mild upper respiratory tract symptoms, which suggests the potential for pre- or oligosymptomatic transmission6-8. There is an urgent need for information on virus replication, immunity and infectivity in specific sites of the body. Here we report a detailed virological analysis of nine cases of COVID-19 that provides proof of active virus replication in tissues of the upper respiratory tract. Pharyngeal virus shedding was very high during the first week of symptoms, with a peak at 7.11 × 108 RNA copies per throat swab on day 4. Infectious virus was readily isolated from samples derived from the throat or lung, but not from stool samples-in spite of high concentrations of virus RNA. Blood and urine samples never yielded virus. Active replication in the throat was confirmed by the presence of viral replicative RNA intermediates in the throat samples. We consistently detected sequence-distinct virus populations in throat and lung samples from one patient, proving independent replication. The shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 7 days in 50% of patients (and by day 14 in all patients), but was not followed by a rapid decline in viral load. COVID-19 can present as a mild illness of the upper respiratory tract. The confirmation of active virus replication in the upper respiratory tract has implications for the containment of COVID-19.
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                Author and article information

                Contributors
                Journal
                Res Sq
                ResearchSquare
                Research Square
                American Journal Experts
                10 September 2020
                : rs.3.rs-70482
                Affiliations
                The University of Texas Medical Branch at Galveston
                University of Texas Medical Branch
                University of Texas Medical Branch
                University of Texas Medical Branch
                University of Texas Medical Branch
                UTMB
                UTMB
                UTMB
                University of Texas Medical Branch
                UTMB
                University of Texas Medical Branch
                University of Texas Medical Branch
                University of Texas Medical Branch
                UTMB
                Gilead
                The University of Texas Health Science Center at Houston
                University of Texas Health Science Center at Houston
                University of Texas Medical Branch
                UTMB
                University of Texas Medical Branch
                University of Texas Medical Branch
                The University of Texas Medical Branch at Galveston
                Author notes

                Author contributions

                Conceptualization, Y.L., V.D.M., X.X., K.S.P., S.C.W., P-Y.S.; Methodology, J.A.P, Y.L., J.L., H.X., B.A.J., K.G.L., X.Z., A.E.M., J.Z., C.R.F.G., A.N.F., V.D.M., X.X., K.S.P., S.C.W., P-Y.S.; Investigation, J.A.P, Y.L., J.L., H.X., B.A.J., K.G.L., X.Z., A.E.M., J.Z., C.R.F.G., D.M., D.S., J.P.B., A.N.F., V.D.M., X.X., K.S.P., S.C.W., P.-Y.S.; Resources, Z.K., Z.A.; Data Curation, J.A.P, Y.L., J.L., H.X., B.A.J., K.G.L., X.Z., A.E.M., J.Z., A.N.F., V.D.M., X.X., K.S.P S.C.W., P.-Y.S.; Writing-Original Draft, J.A.P, Y.L., J.L., X.X., K.S.P., S.C.W., P.-Y.S; Writing-Review & Editing, J.A.P, Y.L., J.L., H.X., B.A.J., K.G.L., X.Z., A.E.M., J.Z., A.N.F., V.D.M., X.X., K.S.P., S.C.W., P.-Y.S.; Supervision, A.N.F., V.D.M., X.X., K.S.P., S.C.W., P.-Y.S.; Funding Acquisition, A.N.F., V.D.M., S.C.W., P.-Y.S..

                Pei-Yong Shi, ( peshi@ 123456UTMB.EDU )
                Author information
                http://orcid.org/0000-0001-5553-1616
                http://orcid.org/0000-0002-2520-7038
                http://orcid.org/0000-0003-0918-016X
                http://orcid.org/0000-0001-8016-8556
                Article
                10.21203/rs.3.rs-70482
                10.21203/rs.3.rs-70482/v1
                7491579
                32935091
                71b524f8-ac39-4fc1-b8e3-05649172af35

                This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.

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                spike protein mutation,d614g,sars-cov-2,mutational impact

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