tetano
Editor, Senior Moderator
J Clin Invest
. 2022 Apr 26;e159062.
doi: 10.1172/JCI159062. Online ahead of print.
An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer
Naveenchandra Suryadevara[SUP] 1 [/SUP], Andrea R Shiakolas[SUP] 2 [/SUP], Laura A VanBlargan[SUP] 3 [/SUP], Elad Binshtein[SUP] 1 [/SUP], Rita E Chen[SUP] 3 [/SUP], James Brett Case[SUP] 3 [/SUP], Kevin J Kramer[SUP] 2 [/SUP], Erica C Armstrong[SUP] 1 [/SUP], Luke Myers[SUP] 1 [/SUP], Andrew Trivette[SUP] 1 [/SUP], Christopher Gainza[SUP] 1 [/SUP], Rachel S Nargi[SUP] 1 [/SUP], Christopher N Selverian[SUP] 4 [/SUP], Edgar Davidson[SUP] 5 [/SUP], Benjamin J Doranz[SUP] 6 [/SUP], Summer M Diaz[SUP] 1 [/SUP], Laura S Handal[SUP] 1 [/SUP], Robert H Carnahan[SUP] 7 [/SUP], Michael S Diamond[SUP] 3 [/SUP], Ivelin S Georgiev[SUP] 1 [/SUP], James E Crowe Jr[SUP] 1 [/SUP]
Affiliations
Abstract
The protective human antibody response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus 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). Here, using the single B cell technology 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 to the NTD supersite commonly are encoded by the IGHV1-24 gene, forming a genetic cluster that represents 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 and possesses a distinct class of functional activity. COV2-3434 disrupted the integrity of S protein trimers, inhibited cell-to-cell spread of virus in culture, and conferred protection in human ACE2 transgenic mice against SARS-CoV-2 challenge. This study provides insight about antibody targeting of the S protein trimer interface region, suggesting this region may be a site of virus vulnerability.
Keywords: Adaptive immunity; Antigen; Immunoglobulins; Immunology; Virology.
. 2022 Apr 26;e159062.
doi: 10.1172/JCI159062. Online ahead of print.
An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer
Naveenchandra Suryadevara[SUP] 1 [/SUP], Andrea R Shiakolas[SUP] 2 [/SUP], Laura A VanBlargan[SUP] 3 [/SUP], Elad Binshtein[SUP] 1 [/SUP], Rita E Chen[SUP] 3 [/SUP], James Brett Case[SUP] 3 [/SUP], Kevin J Kramer[SUP] 2 [/SUP], Erica C Armstrong[SUP] 1 [/SUP], Luke Myers[SUP] 1 [/SUP], Andrew Trivette[SUP] 1 [/SUP], Christopher Gainza[SUP] 1 [/SUP], Rachel S Nargi[SUP] 1 [/SUP], Christopher N Selverian[SUP] 4 [/SUP], Edgar Davidson[SUP] 5 [/SUP], Benjamin J Doranz[SUP] 6 [/SUP], Summer M Diaz[SUP] 1 [/SUP], Laura S Handal[SUP] 1 [/SUP], Robert H Carnahan[SUP] 7 [/SUP], Michael S Diamond[SUP] 3 [/SUP], Ivelin S Georgiev[SUP] 1 [/SUP], James E Crowe Jr[SUP] 1 [/SUP]
Affiliations
- PMID: 35472136
- DOI: 10.1172/JCI159062
Abstract
The protective human antibody response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus 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). Here, using the single B cell technology 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 to the NTD supersite commonly are encoded by the IGHV1-24 gene, forming a genetic cluster that represents 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 and possesses a distinct class of functional activity. COV2-3434 disrupted the integrity of S protein trimers, inhibited cell-to-cell spread of virus in culture, and conferred protection in human ACE2 transgenic mice against SARS-CoV-2 challenge. This study provides insight about antibody targeting of the S protein trimer interface region, suggesting this region may be a site of virus vulnerability.
Keywords: Adaptive immunity; Antigen; Immunoglobulins; Immunology; Virology.