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

Rémy Robinot, Mathieu Hubert, Guilherme Dias Melo, Françoise Lazarini, Timothée Bruel, Nikaïa Smith, Sylvain Levallois, Florence Larrous, Julien Fernandes, Stacy Gellenoncourt, Stéphane Rigaud, Olivier Gorgette, Catherine Thouvenot, Céline Trébeau, Adeline Mallet, Guillaume Duménil, Samy Gobaa, Raphaël Etournay, Pierre-Marie Lledo, Marc Lecuit, Hervé Bourhy, Darragh Duffy, Vincent Michel (), Olivier Schwartz () and Lisa A. Chakrabarti ()
Additional contact information
Rémy Robinot: Institut Pasteur
Mathieu Hubert: Institut Pasteur
Guilherme Dias Melo: Institut Pasteur
Françoise Lazarini: Institut Pasteur
Timothée Bruel: Institut Pasteur
Nikaïa Smith: Institut Pasteur
Sylvain Levallois: Institut Pasteur
Florence Larrous: Institut Pasteur
Julien Fernandes: C2RT, Institut Pasteur
Stacy Gellenoncourt: Institut Pasteur
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
Marc Lecuit: Institut Pasteur
Hervé Bourhy: Institut Pasteur
Darragh Duffy: Institut Pasteur
Vincent Michel: Institut Pasteur, INSERM
Olivier Schwartz: Institut Pasteur
Lisa A. Chakrabarti: Institut Pasteur

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24521-x

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