An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies

• Published in: Cell Vol. 184; no. 13; pp. 3452 - 3466.e18
• Main Authors: Liu, Yafei, Soh, Wai Tuck, Kishikawa, Jun-ichi, Hirose, Mika, Nakayama, Emi E., Li, Songling, Sasai, Miwa, Suzuki, Tatsuya, Tada, Asa, Arakawa, Akemi, Matsuoka, Sumiko, Akamatsu, Kanako, Matsuda, Makoto, Ono, Chikako, Torii, Shiho, Kishida, Kazuki, Jin, Hui, Nakai, Wataru, Arase, Noriko, Nakagawa, Atsushi, Matsumoto, Maki, Nakazaki, Yukoh, Shindo, Yasuhiro, Kohyama, Masako, Tomii, Keisuke, Ohmura, Koichiro, Ohshima, Shiro, Okamoto, Toru, Yamamoto, Masahiro, Nakagami, Hironori, Matsuura, Yoshiharu, Kato, Takayuki, Okada, Masato, Standley, Daron M., Shioda, Tatsuo, Arase, Hisashi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.06.2021
• Subjects: ADE; angiotensin converting enzyme 2; Animals; Antibodies, Monoclonal - immunology; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; antibody-dependent enhancement; Cell Line; Chlorocebus aethiops; COVID-19 - immunology; COVID-19 infection; cryo-electron microscopy; cryo-EM; docking model; HEK293 Cells; Humans; mutational analysis; pathogenicity; Protein Binding - immunology; Protein Domains - immunology; SARS-CoV-2 - immunology; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - immunology; Vero Cells; ADE; docking model; antibody-dependent enhancement; angiotensin converting enzyme 2; cryo-EM; cryo-electron microscopy
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2021.05.032

Antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein prevent SARS-CoV-2 infection. However, the effects of antibodies against other spike protein domains are largely unknown. Here, we screened a series of anti-spike monoclonal antibodies from coronavirus disease 2019 (COVID-19) patients and found that some of antibodies against the N-terminal domain (NTD) induced the open conformation of RBD and thus enhanced the binding capacity of the spike protein to ACE2 and infectivity of SARS-CoV-2. Mutational analysis revealed that all of the infectivity-enhancing antibodies recognized a specific site on the NTD. Structural analysis demonstrated that all infectivity-enhancing antibodies bound to NTD in a similar manner. The antibodies against this infectivity-enhancing site were detected at high levels in severe patients. Moreover, we identified antibodies against the infectivity-enhancing site in uninfected donors, albeit at a lower frequency. These findings demonstrate that not only neutralizing antibodies but also enhancing antibodies are produced during SARS-CoV-2 infection. [Display omitted] •SARS-CoV-2 infectivity is enhanced by specific antibodies independent of the Fc receptor•The open RBD state is induced upon antibody binding to a specific site on the NTD•Divalent bridging of spikes is required to induce the RBD-up state•Infectivity-enhancing antibodies are detected in severe COVID-19 patients A subset of antibodies detected in patients with severe COVID-19 target a specific region of the N-terminal domain of the spike protein and enhance binding of the virus to the ACE2 receptor.