SARS-CoV-2 Bearing a Mutation at the S1/S2 Cleavage Site Exhibits Attenuated Virulence and Confers Protective Immunity

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 t...

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Autores principales:	Michihito Sasaki, Shinsuke Toba, Yukari Itakura, Herman M. Chambaro, Mai Kishimoto, Koshiro Tabata, Kittiya Intaruck, Kentaro Uemura, Takao Sanaki, Akihiko Sato, William W. Hall, Yasuko Orba, Hirofumi Sawa
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	furin cleavage site SARS-CoV-2 spike attenuation neutralizing antibodies Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c64901ae7eca4c998ed00de51843f0a0
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spelling	oai:doaj.org-article:c64901ae7eca4c998ed00de51843f0a02021-11-10T18:37:51ZSARS-CoV-2 Bearing a Mutation at the S1/S2 Cleavage Site Exhibits Attenuated Virulence and Confers Protective Immunity10.1128/mBio.01415-212150-7511https://doaj.org/article/c64901ae7eca4c998ed00de51843f0a02021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01415-21https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE 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.Michihito SasakiShinsuke TobaYukari ItakuraHerman M. ChambaroMai KishimotoKoshiro TabataKittiya IntaruckKentaro UemuraTakao SanakiAkihiko SatoWilliam W. HallYasuko OrbaHirofumi SawaAmerican Society for Microbiologyarticlefurin cleavage siteSARS-CoV-2spikeattenuationneutralizing antibodiesMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	furin cleavage site SARS-CoV-2 spike attenuation neutralizing antibodies Microbiology QR1-502
spellingShingle	furin cleavage site SARS-CoV-2 spike attenuation neutralizing antibodies Microbiology QR1-502 Michihito Sasaki Shinsuke Toba Yukari Itakura Herman M. Chambaro Mai Kishimoto Koshiro Tabata Kittiya Intaruck Kentaro Uemura Takao Sanaki Akihiko Sato William W. Hall Yasuko Orba Hirofumi Sawa SARS-CoV-2 Bearing a Mutation at the S1/S2 Cleavage Site Exhibits Attenuated Virulence and Confers Protective Immunity
description	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. IMPORTANCE 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.
format	article
author	Michihito Sasaki Shinsuke Toba Yukari Itakura Herman M. Chambaro Mai Kishimoto Koshiro Tabata Kittiya Intaruck Kentaro Uemura Takao Sanaki Akihiko Sato William W. Hall Yasuko Orba Hirofumi Sawa
author_facet	Michihito Sasaki Shinsuke Toba Yukari Itakura Herman M. Chambaro Mai Kishimoto Koshiro Tabata Kittiya Intaruck Kentaro Uemura Takao Sanaki Akihiko Sato William W. Hall Yasuko Orba Hirofumi Sawa
author_sort	Michihito Sasaki
title	SARS-CoV-2 Bearing a Mutation at the S1/S2 Cleavage Site Exhibits Attenuated Virulence and Confers Protective Immunity
title_short	SARS-CoV-2 Bearing a Mutation at the S1/S2 Cleavage Site Exhibits Attenuated Virulence and Confers Protective Immunity
title_full	SARS-CoV-2 Bearing a Mutation at the S1/S2 Cleavage Site Exhibits Attenuated Virulence and Confers Protective Immunity
title_fullStr	SARS-CoV-2 Bearing a Mutation at the S1/S2 Cleavage Site Exhibits Attenuated Virulence and Confers Protective Immunity
title_full_unstemmed	SARS-CoV-2 Bearing a Mutation at the S1/S2 Cleavage Site Exhibits Attenuated Virulence and Confers Protective Immunity
title_sort	sars-cov-2 bearing a mutation at the s1/s2 cleavage site exhibits attenuated virulence and confers protective immunity
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/c64901ae7eca4c998ed00de51843f0a0
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SARS-CoV-2 Bearing a Mutation at the S1/S2 Cleavage Site Exhibits Attenuated Virulence and Confers Protective Immunity

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