| Title: | SARS-CoV-2 Bearing a Mutation at the S1/S2 Cleavage Site Exhibits Attenuated Virulence and Confers Protective Immunity |
| Authors: | Sasaki, Michihito Browse this author →KAKEN DB |
| Toba, Shinsuke Browse this author |
| Itakura, Yukari Browse this author |
| Chambaro, Herman M. Browse this author |
| Kishimoto, Mai Browse this author |
| Tabata, Koshiro Browse this author |
| Intaruck, Kittiya Browse this author |
| Uemura, Kentaro Browse this author |
| Sanaki, Takao Browse this author |
| Sato, Akihiro Browse this author |
| Hall, William W. Browse this author |
| Orba, Yasuko Browse this author →KAKEN DB |
| Sawa, Hirofumi Browse this author →KAKEN DB |
| Keywords: | furin cleavage site |
| SARS-CoV-2 |
| spike |
| attenuation |
| neutralizing antibodies |
| Issue Date: | Jul-2021 |
| Publisher: | American Society for Microbiology |
| Journal Title: | mBio |
| Volume: | 12 |
| Issue: | 4 |
| Start Page: | e01415-21 |
| Publisher DOI: | 10.1128/mBio.01415-21 |
| PMID: | 34425707 |
| Abstract: | Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) possesses a discriminative polybasic cleavage motif in its spike protein that is recognized by the host furin protease. Proteolytic cleavage activates the spike protein, thereby affecting both the cellular entry pathway and cell tropism of SARS-CoV-2. Here, we investigated the impact of the furin cleavage site on viral growth and pathogenesis using a hamster animal model infected with SARS-CoV-2 variants bearing mutations at the furin cleavage site (S gene mutants). In the airway tissues of hamsters, the S gene mutants exhibited low growth properties. In contrast to parental pathogenic SARS-CoV-2, hamsters infected with the S gene mutants showed no body weight loss and only a mild inflammatory response, thereby indicating the attenuated variant nature of S gene mutants. This transient infection was sufficient for inducing protective neutralizing antibodies that cross-react with different SARS-CoV-2 lineages. Consequently, hamsters inoculated with S gene mutants showed resistance to subsequent infection with both the parental strain and the currently emerging SARS-CoV-2 variants belonging to lineages B.1.1.7 and P.1. Taken together, our findings revealed that the loss of the furin cleavage site causes attenuation in the airway tissues of hamsters and highlighted the potential benefits of S gene mutants as potential immunogens. SARS-CoV-2 uses its spike protein to enter target cells. The spike protein is cleaved by a host protease, and this event facilitates viral entry and broadens cell tropism. In this study, we employed SARS-CoV-2 mutants lacking the S protein cleavage site and characterized their growth and pathogenicity using hamsters, a laboratory animal model for SARS-CoV-2 infection. These mutants exerted low pathogenicity but induced sufficient levels of neutralizing antibodies in hamsters, which protected hamsters from rechallenge with pathogenic clinical SARS-CoV-2 strains. These virus mutants may be used as protective immunogens against SARS-CoV-2 infection. |
| Rights: | https://creativecommons.org/licenses/by/4.0/ |
| Type: | article |
| URI: | http://hdl.handle.net/2115/82642 |
| Appears in Collections: | 人獣共通感染症国際共同研究所 (International Institute for Zoonosis Control) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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