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Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis

Author

Listed:
  • Bryan A. Johnson

    (University of Texas Medical Branch)

  • Xuping Xie

    (University of Texas Medical Branch)

  • Adam L. Bailey

    (Washington University School of Medicine)

  • Birte Kalveram

    (University of Texas Medical Branch)

  • Kumari G. Lokugamage

    (University of Texas Medical Branch)

  • Antonio Muruato

    (University of Texas Medical Branch)

  • Jing Zou

    (University of Texas Medical Branch)

  • Xianwen Zhang

    (University of Texas Medical Branch)

  • Terry Juelich

    (University of Texas Medical Branch)

  • Jennifer K. Smith

    (University of Texas Medical Branch)

  • Lihong Zhang

    (University of Texas Medical Branch)

  • Nathen Bopp

    (University of Texas Medical Branch)

  • Craig Schindewolf

    (University of Texas Medical Branch)

  • Michelle Vu

    (University of Texas Medical Branch)

  • Abigail Vanderheiden

    (Emory University School of Medicine
    Emory University School of Medicine)

  • Emma S. Winkler

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Daniele Swetnam

    (University of Texas Medical Branch)

  • Jessica A. Plante

    (University of Texas Medical Branch)

  • Patricia Aguilar

    (University of Texas Medical Branch)

  • Kenneth S. Plante

    (University of Texas Medical Branch)

  • Vsevolod Popov

    (University of Texas Medical Branch)

  • Benhur Lee

    (Icahn School of Medicine at Mount Sinai)

  • Scott C. Weaver

    (University of Texas Medical Branch
    University of Texas Medical Branch)

  • Mehul S. Suthar

    (Emory University School of Medicine
    Emory University School of Medicine
    Yerkes National Primate Research Center)

  • Andrew L. Routh

    (University of Texas Medical Branch)

  • Ping Ren

    (University of Texas Medical Branch)

  • Zhiqiang Ku

    (University of Texas Health Science Center at Houston)

  • Zhiqiang An

    (University of Texas Health Science Center at Houston)

  • Kari Debbink

    (Department of Natural Sciences Bowie State University)

  • Michael S. Diamond

    (Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine)

  • Pei-Yong Shi

    (University of Texas Medical Branch
    University of Texas Medical Branch)

  • Alexander N. Freiberg

    (University of Texas Medical Branch
    University of Texas Medical Branch)

  • Vineet D. Menachery

    (University of Texas Medical Branch
    University of Texas Medical Branch)

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.

Suggested Citation

  • Bryan A. Johnson & Xuping Xie & Adam L. Bailey & Birte Kalveram & Kumari G. Lokugamage & Antonio Muruato & Jing Zou & Xianwen Zhang & Terry Juelich & Jennifer K. Smith & Lihong Zhang & Nathen Bopp & C, 2021. "Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis," Nature, Nature, vol. 591(7849), pages 293-299, March.
    • Handle: RePEc:nat:nature:v:591:y:2021:i:7849:d:10.1038_s41586-021-03237-4
    DOI: 10.1038/s41586-021-03237-4
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    Cited by:

    1. Shufeng Liu & Charles B. Stauft & Prabhuanand Selvaraj & Prabha Chandrasekaran & Felice D’Agnillo & Chao-Kai Chou & Wells W. Wu & Christopher Z. Lien & Clement A. Meseda & Cyntia L. Pedro & Matthew F., 2022. "Intranasal delivery of a rationally attenuated SARS-CoV-2 is immunogenic and protective in Syrian hamsters," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Shelly J. Robertson & Olivia Bedard & Kristin L. McNally & Carl Shaia & Chad S. Clancy & Matthew Lewis & Rebecca M. Broeckel & Abhilash I. Chiramel & Jeffrey G. Shannon & Gail L. Sturdevant & Rebecca , 2023. "Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Shengjun Wang & Wei Ran & Lingyu Sun & Qingchi Fan & Yuanqi Zhao & Bowen Wang & Jinghong Yang & Yuqi He & Ying Wu & Yuanyuan Wang & Luoyi Chen & Arpaporn Chuchuay & Yuyu You & Xinhai Zhu & Xiaojuan Wa, 2024. "Sequential glycosylations at the multibasic cleavage site of SARS-CoV-2 spike protein regulate viral activity," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Marziah Hashimi & T. Andrew Sebrell & Jodi F. Hedges & Deann Snyder & Katrina N. Lyon & Stephanie D. Byrum & Samuel G. Mackintosh & Dan Crowley & Michelle D. Cherne & David Skwarchuk & Amanda Robison , 2023. "Antiviral responses in a Jamaican fruit bat intestinal organoid model of SARS-CoV-2 infection," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    5. Yang Liu & Xianwen Zhang & Jianying Liu & Hongjie Xia & Jing Zou & Antonio E. Muruato & Sivakumar Periasamy & Chaitanya Kurhade & Jessica A. Plante & Nathen E. Bopp & Birte Kalveram & Alexander Bukrey, 2022. "A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    6. Sebastian Weigang & Jonas Fuchs & Gert Zimmer & Daniel Schnepf & Lisa Kern & Julius Beer & Hendrik Luxenburger & Jakob Ankerhold & Valeria Falcone & Janine Kemming & Maike Hofmann & Robert Thimme & Ch, 2021. "Within-host evolution of SARS-CoV-2 in an immunosuppressed COVID-19 patient as a source of immune escape variants," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    7. Alexander J. Pak & Alvin Yu & Zunlong Ke & John A. G. Briggs & Gregory A. Voth, 2022. "Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    8. Palash Sashittal & Chuanyi Zhang & Jian Peng & Mohammed El-Kebir, 2021. "Jumper enables discontinuous transcript assembly in coronaviruses," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    9. Wenjuan Dong & Jing Wang & Lei Tian & Jianying Zhang & Erik W. Settles & Chao Qin & Daniel R. Steinken-Kollath & Ashley N. Itogawa & Kimberly R. Celona & Jinhee Yi & Mitchell Bryant & Heather Mead & S, 2023. "Factor Xa cleaves SARS-CoV-2 spike protein to block viral entry and infection," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    10. Melanie Koehler & Ankita Ray & Rodrigo A. Moreira & Blinera Juniku & Adolfo B. Poma & David Alsteens, 2021. "Molecular insights into receptor binding energetics and neutralization of SARS-CoV-2 variants," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    11. Oskar Staufer & Kapil Gupta & Jochen Estebano Hernandez Bücher & Fabian Kohler & Christian Sigl & Gunjita Singh & Kate Vasileiou & Ana Yagüe Relimpio & Meline Macher & Sebastian Fabritz & Hendrik Diet, 2022. "Synthetic virions reveal fatty acid-coupled adaptive immunogenicity of SARS-CoV-2 spike glycoprotein," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    12. Christopher Cyrus Kuhn & Nirakar Basnet & Satish Bodakuntla & Pelayo Alvarez-Brecht & Scott Nichols & Antonio Martinez-Sanchez & Lorenzo Agostini & Young-Min Soh & Junichi Takagi & Christian Biertümpf, 2023. "Direct Cryo-ET observation of platelet deformation induced by SARS-CoV-2 spike protein," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    13. Cathrine Scheepers & Josie Everatt & Daniel G. Amoako & Houriiyah Tegally & Constantinos Kurt Wibmer & Anele Mnguni & Arshad Ismail & Boitshoko Mahlangu & Bronwen E. Lambson & Darren P. Martin & Eduan, 2022. "Emergence and phenotypic characterization of the global SARS-CoV-2 C.1.2 lineage," Nature Communications, Nature, vol. 13(1), pages 1-9, December.

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