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The ACE2-binding Interface of SARS-CoV-2 Spike Inherently Deflects Immune Recognition

Authors
  • Hattori, Takamitsu1, 2
  • Koide, Akiko1, 3
  • Noval, Maria G.4
  • Panchenko, Tatyana1
  • Romero, Larizbeth A.2
  • Teng, Kai Wen1
  • Tada, Takuya4
  • Landau, Nathaniel R.4
  • Stapleford, Kenneth A.4
  • Koide, Shohei1, 2
  • 1 Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA
  • 2 Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY 10016, USA
  • 3 Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
  • 4 Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA
Type
Published Article
Journal
Journal of Molecular Biology
Publisher
Elsevier
Publication Date
Dec 11, 2020
Volume
433
Issue
3
Pages
166748–166748
Identifiers
DOI: 10.1016/j.jmb.2020.166748
PMID: 33310017
PMCID: PMC7833242
Source
PubMed Central
Keywords
Disciplines
  • Communication
License
Unknown

Abstract

The COVID-19 pandemic remains a global threat, and host immunity remains the main mechanism of protection against the disease. The spike protein on the surface of SARS-CoV-2 is a major antigen and its engagement with human ACE2 receptor plays an essential role in viral entry into host cells. Consequently, antibodies targeting the ACE2-interacting surface (ACE2IS) located in the receptor-binding domain (RBD) of the spike protein can neutralize the virus. However, the understanding of immune responses to SARS-CoV-2 is still limited, and it is unclear how the virus protects this surface from recognition by antibodies. Here, we designed an RBD mutant that disrupts the ACE2IS and used it to characterize the prevalence of antibodies directed to the ACE2IS from convalescent sera of 94 COVID-19-positive patients. We found that only a small fraction of RBD-binding antibodies targeted the ACE2IS. To assess the immunogenicity of different parts of the spike protein, we performed in vitro antibody selection for the spike and the RBD proteins using both unbiased and biased selection strategies. Intriguingly, unbiased selection yielded antibodies that predominantly targeted regions outside the ACE2IS, whereas ACE2IS-binding antibodies were readily identified from biased selection designed to enrich such antibodies. Furthermore, antibodies from an unbiased selection using the RBD preferentially bound to the surfaces that are inaccessible in the context of whole spike protein. These results suggest that the ACE2IS has evolved less immunogenic than the other regions of the spike protein, which has important implications in the development of vaccines against SARS-CoV-2.

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