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Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis.
Johnson, Bryan A; Xie, Xuping; Bailey, Adam L; Kalveram, Birte; Lokugamage, Kumari G; Muruato, Antonio; Zou, Jing; Zhang, Xianwen; Juelich, Terry; Smith, Jennifer K; Zhang, Lihong; Bopp, Nathen; Schindewolf, Craig; Vu, Michelle; Vanderheiden, Abigail; Winkler, Emma S; Swetnam, Daniele; Plante, Jessica A; Aguilar, Patricia; Plante, Kenneth S; Popov, Vsevolod; Lee, Benhur; Weaver, Scott C; Suthar, Mehul S; Routh, Andrew L; Ren, Ping; Ku, Zhiqiang; An, Zhiqiang; Debbink, Kari; Diamond, Michael S; Shi, Pei-Yong; Freiberg, Alexander N; Menachery, Vineet D.
  • Johnson BA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • Xie X; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
  • Bailey AL; Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
  • Kalveram B; Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
  • Lokugamage KG; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • Muruato A; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • Zou J; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
  • Zhang X; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
  • Juelich T; Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
  • Smith JK; Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
  • Zhang L; Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
  • Bopp N; Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
  • Schindewolf C; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • Vu M; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • Vanderheiden A; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
  • Winkler ES; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.
  • Swetnam D; Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
  • Plante JA; Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
  • Aguilar P; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
  • Plante KS; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • Popov V; Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
  • Lee B; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • Weaver SC; Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
  • Suthar MS; Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Routh AL; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
  • Ren P; Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
  • Ku Z; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
  • An Z; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.
  • Debbink K; Yerkes National Primate Research Center, Atlanta, GA, USA.
  • Diamond MS; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
  • Shi PY; Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
  • Freiberg AN; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, USA.
  • Menachery VD; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, USA.
Nature ; 591(7849): 293-299, 2021 03.
Article in English | MEDLINE | ID: covidwho-1046014
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-a new coronavirus that has led to a worldwide pandemic1-has a furin cleavage site (PRRAR) in its spike protein that is absent in other group-2B coronaviruses2. To explore whether the furin cleavage site contributes to infection and pathogenesis in this virus, we generated a mutant SARS-CoV-2 that lacks the furin cleavage site (ΔPRRA). Here we report that replicates of ΔPRRA SARS-CoV-2 had faster kinetics, improved fitness in Vero E6 cells and reduced spike protein processing, as compared to parental SARS-CoV-2. However, the ΔPRRA mutant had reduced replication in a human respiratory cell line and was attenuated in both hamster and K18-hACE2 transgenic mouse models of SARS-CoV-2 pathogenesis. Despite reduced disease, the ΔPRRA mutant conferred protection against rechallenge with the parental SARS-CoV-2. Importantly, the neutralization values of sera from patients with coronavirus disease 2019 (COVID-19) and monoclonal antibodies against the receptor-binding domain of SARS-CoV-2 were lower against the ΔPRRA mutant than against parental SARS-CoV-2, probably owing to an increased ratio of particles to plaque-forming units in infections with the former. Together, our results demonstrate a critical role for the furin cleavage site in infection with SARS-CoV-2 and highlight the importance of this site for evaluating the neutralization activities of antibodies.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Furin / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / COVID-19 / Mutation Type of study: Experimental Studies Limits: Animals / Female / Humans / Male Language: English Journal: Nature Year: 2021 Document Type: Article Affiliation country: S41586-021-03237-4

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Furin / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / COVID-19 / Mutation Type of study: Experimental Studies Limits: Animals / Female / Humans / Male Language: English Journal: Nature Year: 2021 Document Type: Article Affiliation country: S41586-021-03237-4