B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV.

Antibodies, Monoclonal / chemistry Antibodies, Neutralizing / blood Antibodies, Viral / blood Antigen-Antibody Complex / chemistry Antigen-Antibody Reactions B-Lymphocytes / cytology COVID-19 / pathology Cryoelectron Microscopy Crystallography, X-Ray Gene Expression Profiling Humans Immunoglobulin A / immunology Immunoglobulin Variable Region / chemistry Protein Domains / immunology Protein Multimerization Protein Structure, Quaternary SARS-CoV-2 / immunology Sequence Analysis, RNA Spike Glycoprotein, Coronavirus / chemistry
COVID-19 SARS-CoV cross-neutralization cryo-electron microscopy disordered CDRH3 memory B cells monoclonal antibodies single B cell genomics

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
10 06 2021
Historique:
received: 18 12 2020
revised: 26 02 2021
accepted: 19 04 2021
pubmed: 21 5 2021
medline: 30 6 2021
entrez: 20 5 2021
Statut: ppublish

Résumé

Monoclonal antibodies (mAbs) are a focus in vaccine and therapeutic design to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. Here, we combined B cell sorting with single-cell VDJ and RNA sequencing (RNA-seq) and mAb structures to characterize B cell responses against SARS-CoV-2. We show that the SARS-CoV-2-specific B cell repertoire consists of transcriptionally distinct B cell populations with cells producing potently neutralizing antibodies (nAbs) localized in two clusters that resemble memory and activated B cells. Cryo-electron microscopy structures of selected nAbs from these two clusters complexed with SARS-CoV-2 spike trimers show recognition of various receptor-binding domain (RBD) epitopes. One of these mAbs, BG10-19, locks the spike trimer in a closed conformation to potently neutralize SARS-CoV-2, the recently arising mutants B.1.1.7 and B.1.351, and SARS-CoV and cross-reacts with heterologous RBDs. Together, our results characterize transcriptional differences among SARS-CoV-2-specific B cells and uncover cross-neutralizing Ab targets that will inform immunogen and therapeutic design against coronaviruses.

Identifiants

DOI: 10.1016/j.cell.2021.04.032 PMID: 34015271 PMC: PMC8064835
pubmed: 34015271
pii: S0092-8674(21)00535-3
doi: 10.1016/j.cell.2021.04.032
pmc: PMC8064835
mid: NIHMS1696927
pii:
doi:

Substances chimiques

Antibodies, Monoclonal 0
Antibodies, Neutralizing 0
Antibodies, Viral 0
Antigen-Antibody Complex 0
Immunoglobulin A 0
Immunoglobulin Variable Region 0
Spike Glycoprotein, Coronavirus 0
spike protein, SARS-CoV-2 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

3205-3221.e24

Subventions

Organisme : NIDDK NIH HHS
ID : P30 DK043351
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI138938
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI069412
Pays : United States
Organisme : NIAID NIH HHS
ID : P50 AI150464
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI142784
Pays : United States
Organisme : NIDA NIH HHS
ID : DP1 DA046100
Pays : United States
Organisme : NIAID NIH HHS
ID : K08 AI120898
Pays : United States
Organisme : NIDDK NIH HHS
ID : RC2 DK114784
Pays : United States

Informations de copyright

Copyright © 2021 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests A provisional patent for the novel SARS-CoV-2 mAbs described in this study has been filed. The authors listed on that application are R.J.X., J.F.S., C.O.B., P.J.B., and B.E. The Broad Institute has filed multiple patents in the area of single cell RNA-seq on which A.R. and O.R.-R. are named inventors. Rockefeller University has applied for a patent relating to the replication competent VSV/SARS-CoV-2 chimeric virus on which Y.W., T.H., and P.D.B. are listed as inventors (US patent 63/036,124). R.J.X. is co-founder and equity holder of Jnana Therapeutics. R.J.X. and A.R. are co-founders and equity holders of Celsius Therapeutics. A.R. is an equity holder in Immunitas and was an SAB member of ThermoFisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics, and Asimov. A.R. and O.R.-R. are employees of Genentech (member of the Roche Group) since August and October 2020, respectively. These companies did not provide support for this work.

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Auteurs

Johannes F Scheid (JF)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Christopher O Barnes (CO)

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.

Basak Eraslan (B)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.

Andrew Hudak (A)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.

Jennifer R Keeffe (JR)

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.

Lisa A Cosimi (LA)

Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Eric M Brown (EM)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Frauke Muecksch (F)

Laboratory of Molecular Virology, The Rockefeller University, New York, NY 10065, USA.

Yiska Weisblum (Y)

Laboratory of Molecular Virology, The Rockefeller University, New York, NY 10065, USA.

Shuting Zhang (S)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.

Toni Delorey (T)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Ann E Woolley (AE)

Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Fadi Ghantous (F)

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.

Sung-Moo Park (SM)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.

Devan Phillips (D)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Betsabeh Tusi (B)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.

Kathryn E Huey-Tubman (KE)

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.

Alexander A Cohen (AA)

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.

Priyanthi N P Gnanapragasam (PNP)

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.

Kara Rzasa (K)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.

Theodora Hatziioanno (T)

Laboratory of Molecular Virology, The Rockefeller University, New York, NY 10065, USA.

Michael A Durney (MA)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.

Xiebin Gu (X)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.

Takuya Tada (T)

Department of Microbiology, NYU Grossman School of Medicine, New York, NY 10016, USA.

Nathaniel R Landau (NR)

Department of Microbiology, NYU Grossman School of Medicine, New York, NY 10016, USA.

Anthony P West (AP)

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.

Orit Rozenblatt-Rosen (O)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Michael S Seaman (MS)

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.

Lindsey R Baden (LR)

Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Daniel B Graham (DB)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Jacques Deguine (J)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.

Paul D Bieniasz (PD)

Laboratory of Molecular Virology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.

Aviv Regev (A)

Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.

Deborah Hung (D)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Pamela J Bjorkman (PJ)

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: bjorkman@caltech.edu.

Ramnik J Xavier (RJ)

Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: xavier@molbio.mgh.harvard.edu.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Anticorps monoclonaux › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Anticorps neutralisants › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Anticorps antiviraux › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Facteurs biologiques › Antigènes › Complexe antigène-anticorps › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Phénomènes du système immunitaire › Réaction antigène-anticorps › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes B › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Infections de l'appareil respiratoire › Pneumopathie infectieuse › Pneumopathie virale › COVID-19 › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Techniques d'investigation › Microscopie électronique › Cryomicroscopie électronique › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Cristallographie aux rayons X › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de profil d'expression de gènes › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Isotypes des immunoglobulines › Immunoglobuline A › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Région variable d'immunoglobuline › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Structure tertiaire des protéines › Domaines protéiques › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Multimérisation de protéines › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Structure quaternaire des protéines › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Virus › Virus à ARN › Virus à ARN à brin positif › Nidovirales › Coronaviridae › Coronavirus › Betacoronavirus › Virus du SRAS › SARS-CoV-2 › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ARN › B cell genomics behind cross-neutralization of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines virales › Protéines virales structurales › Protéines de l'enveloppe virale › Protéines de fusion virale › Glycoprotéine de spicule des coronavirus › B cell genomics behind cross-neutralization of...