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      Role of IgM and IgA Antibodies in the Neutralization of SARS-CoV-2

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          Abstract

          Background:

          SARS-CoV-2 has infected millions of people globally. Virus infection requires the receptor-binding domain (RBD) of the spike protein. Although studies have demonstrated anti-spike and - RBD antibodies to be protective in animal models, and convalescent plasma as a promising therapeutic option, little is known about immunoglobulin (Ig) isotypes capable of blocking infection.

          Methods:

          We studied spike- and RBD-specific Ig isotypes in convalescent and acute plasma/sera using a multiplex bead assay. We also determined virus neutralization activities in plasma, sera, and purified Ig fractions using a VSV pseudovirus assay.

          Results:

          Spike- and RBD-specific IgM, IgG1, and IgA1 were produced by all or nearly all subjects at variable levels and detected early after infection. All samples displayed neutralizing activity. Regression analyses revealed that IgM and IgG1 contributed most to neutralization, consistent with IgM and IgG fractions’ neutralization potency. IgA also exhibited neutralizing activity, but with lower potency.

          Conclusion:

          IgG, IgM and IgA are critical components of convalescent plasma used for COVID-19 treatment.

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          Most cited references48

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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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            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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                Author and article information

                Journal
                medRxiv
                MEDRXIV
                medRxiv
                Cold Spring Harbor Laboratory
                21 December 2020
                : 2020.08.18.20177303
                Affiliations
                [1 ]Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY USA.
                [2 ]James J. Peters VA Medical Center, Bronx, NY, USA.
                [3 ]Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
                [4 ]Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
                [5 ]Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
                [6 ]Division of Infectious Diseases, Department of Medicine, Mount Sinai West and Morningside, NY, USA.
                [7 ]Pulmonary and Critical Care Medicine, Mount Sinai West, NY, USA.
                [8 ]Department of Environment Medicine, NYU School of Medicine, New York, NY, USA
                Author notes

                Author contributions

                J.K., S.W., G.E-A., S.Z-P., and C.E.H. wrote and edited the manuscript. S.W., J.K., C.E.H., and S.Z-P. designed the experiments. J.K., S.W., V.I., X.L. performed the experiments and collected the data. J.K., A.N., S.Z-P. and C.E.H. analyzed the data. K.Y.O., C.S., S.I., C-T.H., F.A., and B.L. provided protocols, antigens, cells and pseudovirus stocks. G.E-A., I.B., S.A., J.C.B., E.M.K., J.S., S.L., D.J., and M.B-G. provided specimens. All authors read and approved the final manuscript.

                [* ]Co-corresponding author: Contact: catarina.hioe@ 123456mssm.edu , catarina.hioe@ 123456va.gov
                Article
                10.1101/2020.08.18.20177303
                7654883
                33173891
                8d6bea72-eb7b-4154-9880-d6ce12821aad

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.

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                sars-cov-2,covid-19,antibody isotypes,neutralization,convalescent plasma

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