TY - JOUR
T1 - An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer
AU - Suryadevara, Naveenchandra
AU - Shiakolas, Andrea R.
AU - VanBlargan, Laura A.
AU - Binshtein, Elad
AU - Chen, Rita E.
AU - Case, James Brett
AU - Kramer, Kevin J.
AU - Armstrong, Erica C.
AU - Myers, Luke
AU - Trivette, Andrew
AU - Gainza, Christopher
AU - Nargi, Rachel S.
AU - Selverian, Christopher N.
AU - Davidson, Edgar
AU - Doranz, Benjamin J.
AU - Diaz, Summer M.
AU - Handal, Laura S.
AU - Carnahan, Robert H.
AU - Diamond, Michael S.
AU - Georgiev, Ivelin S.
AU - Crowe, James E.
N1 - Publisher Copyright:
© 2022, Suryadevara et al.
PY - 2022/6/1
Y1 - 2022/6/1
N2 - The protective human antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) focuses on the spike (S) protein, which decorates the virion surface and mediates cell binding and entry. Most SARS-CoV-2 protective antibodies target the receptor-binding domain or a single dominant epitope (“supersite”) on the N-terminal domain (NTD). Using the single B cell technology called linking B cell receptor to antigen specificity through sequencing (LIBRA-Seq), we isolated a large panel of NTD-reactive and SARS-CoV-2–neutralizing antibodies from an individual who had recovered from COVID-19. We found that neutralizing antibodies against the NTD supersite were commonly encoded by the IGHV1-24 gene, forming a genetic cluster representing a public B cell clonotype. However, we also discovered a rare human antibody, COV2-3434, that recognizes a site of vulnerability on the SARS-CoV-2 S protein in the trimer interface (TI) and possesses a distinct class of functional activity. COV2-3434 disrupted the integrity of S protein trimers, inhibited the cell-to-cell spread of the virus in culture, and conferred protection in human angiotensin-converting enzyme 2–transgenic (ACE2-transgenic) mice against the SARS-CoV-2 challenge. This study provides insight into antibody targeting of the S protein TI region, suggesting this region may be a site of virus vulnerability.
AB - The protective human antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) focuses on the spike (S) protein, which decorates the virion surface and mediates cell binding and entry. Most SARS-CoV-2 protective antibodies target the receptor-binding domain or a single dominant epitope (“supersite”) on the N-terminal domain (NTD). Using the single B cell technology called linking B cell receptor to antigen specificity through sequencing (LIBRA-Seq), we isolated a large panel of NTD-reactive and SARS-CoV-2–neutralizing antibodies from an individual who had recovered from COVID-19. We found that neutralizing antibodies against the NTD supersite were commonly encoded by the IGHV1-24 gene, forming a genetic cluster representing a public B cell clonotype. However, we also discovered a rare human antibody, COV2-3434, that recognizes a site of vulnerability on the SARS-CoV-2 S protein in the trimer interface (TI) and possesses a distinct class of functional activity. COV2-3434 disrupted the integrity of S protein trimers, inhibited the cell-to-cell spread of the virus in culture, and conferred protection in human angiotensin-converting enzyme 2–transgenic (ACE2-transgenic) mice against the SARS-CoV-2 challenge. This study provides insight into antibody targeting of the S protein TI region, suggesting this region may be a site of virus vulnerability.
UR - http://www.scopus.com/inward/record.url?scp=85131217292&partnerID=8YFLogxK
U2 - 10.1172/JCI159062
DO - 10.1172/JCI159062
M3 - Article
C2 - 35472136
AN - SCOPUS:85131217292
SN - 0021-9738
VL - 132
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
M1 - e159062
ER -