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SARS-CoV-2 infection induces the dedifferentiation of multiciliated cells and impairs mucociliary clearance

Author

Listed:
  • Rémy Robinot

    (Institut Pasteur
    UMR 3569 CNRS)

  • Mathieu Hubert

    (Institut Pasteur
    UMR 3569 CNRS)

  • Guilherme Dias Melo

    (Institut Pasteur)

  • Françoise Lazarini

    (Institut Pasteur
    UMR 3571 CNRS)

  • Timothée Bruel

    (Institut Pasteur
    UMR 3569 CNRS)

  • Nikaïa Smith

    (Institut Pasteur)

  • Sylvain Levallois

    (Institut Pasteur
    INSERM U1117)

  • Florence Larrous

    (Institut Pasteur)

  • Julien Fernandes

    (C2RT, Institut Pasteur)

  • Stacy Gellenoncourt

    (Institut Pasteur
    UMR 3569 CNRS)

  • Stéphane Rigaud

    (C2RT, Institut Pasteur)

  • Olivier Gorgette

    (Institut Pasteur)

  • Catherine Thouvenot

    (Institut Pasteur)

  • Céline Trébeau

    (Institut Pasteur, INSERM)

  • Adeline Mallet

    (Institut Pasteur)

  • Guillaume Duménil

    (Institut Pasteur)

  • Samy Gobaa

    (Institut Pasteur)

  • Raphaël Etournay

    (Institut Pasteur, INSERM)

  • Pierre-Marie Lledo

    (Institut Pasteur
    UMR 3571 CNRS)

  • Marc Lecuit

    (Institut Pasteur
    INSERM U1117
    Institut Imagine)

  • Hervé Bourhy

    (Institut Pasteur)

  • Darragh Duffy

    (Institut Pasteur)

  • Vincent Michel

    (Institut Pasteur, INSERM)

  • Olivier Schwartz

    (Institut Pasteur
    UMR 3569 CNRS
    Vaccine Research Institute)

  • Lisa A. Chakrabarti

    (Institut Pasteur
    UMR 3569 CNRS)

Abstract

Understanding how SARS-CoV-2 spreads within the respiratory tract is important to define the parameters controlling the severity of COVID-19. Here we examine the functional and structural consequences of SARS-CoV-2 infection in a reconstructed human bronchial epithelium model. SARS-CoV-2 replication causes a transient decrease in epithelial barrier function and disruption of tight junctions, though viral particle crossing remains limited. Rather, SARS-CoV-2 replication leads to a rapid loss of the ciliary layer, characterized at the ultrastructural level by axoneme loss and misorientation of remaining basal bodies. Downregulation of the master regulator of ciliogenesis Foxj1 occurs prior to extensive cilia loss, implicating this transcription factor in the dedifferentiation of ciliated cells. Motile cilia function is compromised by SARS-CoV-2 infection, as measured in a mucociliary clearance assay. Epithelial defense mechanisms, including basal cell mobilization and interferon-lambda induction, ramp up only after the initiation of cilia damage. Analysis of SARS-CoV-2 infection in Syrian hamsters further demonstrates the loss of motile cilia in vivo. This study identifies cilia damage as a pathogenic mechanism that could facilitate SARS-CoV-2 spread to the deeper lung parenchyma.

Suggested Citation

  • Rémy Robinot & Mathieu Hubert & Guilherme Dias Melo & Françoise Lazarini & Timothée Bruel & Nikaïa Smith & Sylvain Levallois & Florence Larrous & Julien Fernandes & Stacy Gellenoncourt & Stéphane Riga, 2021. "SARS-CoV-2 infection induces the dedifferentiation of multiciliated cells and impairs mucociliary clearance," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24521-x
    DOI: 10.1038/s41467-021-24521-x
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    Cited by:

    1. Federico Armando & Georg Beythien & Franziska K. Kaiser & Lisa Allnoch & Laura Heydemann & Malgorzata Rosiak & Svenja Becker & Mariana Gonzalez-Hernandez & Mart M. Lamers & Bart L. Haagmans & Kate Gui, 2022. "SARS-CoV-2 Omicron variant causes mild pathology in the upper and lower respiratory tract of hamsters," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Mark E. Becker & Laura Martin-Sancho & Lacy M. Simons & Michael D. McRaven & Sumit K. Chanda & Judd F. Hultquist & Thomas J. Hope, 2024. "Live imaging of airway epithelium reveals that mucociliary clearance modulates SARS-CoV-2 spread," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Catherine F. Hatton & Rachel A. Botting & Maria Emilia Dueñas & Iram J. Haq & Bernard Verdon & Benjamin J. Thompson & Jarmila Stremenova Spegarova & Florian Gothe & Emily Stephenson & Aaron I. Gardner, 2021. "Delayed induction of type I and III interferons mediates nasal epithelial cell permissiveness to SARS-CoV-2," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    4. Sungmin Moon & Seunghan Han & In-Hwan Jang & Jaechan Ryu & Min-Seok Rha & Hyung-Ju Cho & Sang Sun Yoon & Ki Taek Nam & Chang-Hoon Kim & Man-Seong Park & Je Kyung Seong & Won-Jae Lee & Joo-Heon Yoon & , 2024. "Airway epithelial CD47 plays a critical role in inducing influenza virus-mediated bacterial super-infection," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Delphine Planas & Isabelle Staropoli & Vincent Michel & Frederic Lemoine & Flora Donati & Matthieu Prot & Francoise Porrot & Florence Guivel-Benhassine & Banujaa Jeyarajah & Angela Brisebarre & Océane, 2024. "Distinct evolution of SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 lineages combining increased fitness and antibody evasion," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Andreia L. Pinto & Ranjit K. Rai & Jonathan C. Brown & Paul Griffin & James R. Edgar & Anand Shah & Aran Singanayagam & Claire Hogg & Wendy S. Barclay & Clare E. Futter & Thomas Burgoyne, 2022. "Ultrastructural insight into SARS-CoV-2 entry and budding in human airway epithelium," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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