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

Autor: Robinot, Rémy, Hubert, Mathieu, de Melo, Guilherme Dias, Lazarini, Françoise, Bruel, Timothée, Smith, Nikaïa, Levallois, Sylvain, Larrous, Florence, Fernandes, Julien, Gellenoncourt, Stacy, Rigaud, Stéphane, Gorgette, Olivier, Thouvenot, Catherine, Trébeau, Céline, Mallet, Adeline, Duménil, Guillaume, Gobaa, Samy, Etournay, Raphaël, Lledo, Pierre-Marie, Lecuit, Marc, Bourhy, Hervé, Duffy, Darragh, Michel, Vincent, Schwartz, Olivier, Chakrabarti, Lisa
Přispěvatelé: Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Institut Pasteur [Paris], Perception et Mémoire / Perception and Memory, Immunologie Translationnelle - Translational Immunology lab, Biologie des Infections - Biology of Infection, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), BioImagerie Photonique – Photonic BioImaging (UTechS PBI), Hub d'analyse d'images - Image Analysis Hub (Platform) (IAH), Institut de l'Audition [Paris] (IDA), Plateforme technologique Biomatériaux et Microfluidique - Biomaterials and Microfluidics technologic Platform, Service des Maladies infectieuses et tropicales [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by: Institut Pasteur TASK FORCE SARS COV2 (TROPICORO project), the Urgence COVID-19 Fundraising Campaign of Institut Pasteur (COROCHIP project), DIM ELICIT Region Ile-de-France, and Agence Nationale de Recherche sur le SIDA et les Maladies Infectieuses Emergentes (ANRS, project 19052) (L.A.C.), the Vaccine Research Institute (ANR-10-LABX-77), ANRS, Labex IBEID (ANR-10-LABX-62-IBEID), the French National Research Agency (ANR, projects 'TIMTAMDEN' ANR-14-CE14-0029, 'CHIKV-Viro-Immuno' ANR-14-CE14-0015-01), the Gilead HIV cure program, ANR/Fondation pour la Recherche Médicale (FRM) Flash Covid PROTEO-SARS-CoV-2 and IDISCOVR (O.S.), Institut Pasteur TASK FORCE SARS COV2 and ANR Flash Covid CoVarImm (D.D.), Institut Pasteur TASK FORCE SARS COV2 (Neuro-Covid project) (H.B.). The Lledo lab is supported by the life insurance company 'AG2R-La-Mondiale'. The UtechS Photonic BioImaging (Imagopole) and the UtechS Ultrastructural BioImaging (UBI) are supported by the ANR (France BioImaging, ANR-10–INSB–04, Investments for the Future). R.R. is the recipient of a Sidaction fellowship, N.S. of a Pasteur-Roux-Cantarini fellowship, and St.G. of a MESR/Ecole Doctorale B3MI, Université de Paris fellowship. S.L. is supported by FRM (fellowship ECO201906009119) and by 'Ecole Doctorale FIRE—Programme Bettencourt'., We thank Florence Guivel-Benhassine for help with virus titration, Charlotte Calvet for help with sample preparation for scanning electron microscopy, Sylvie Van der Werf for the SARS-CoV-2 isolate used in this study, and Nicolas Escriou for the gift of a SARS-CoV-2 spike antibody., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Vaccine Research Institute [Créteil, France] (VRI), Vougny, Marie-Christine, Laboratoires d'excellence - Initiative for the creation of a Vaccine Research Institute - - VRI2010 - ANR-10-LABX-0077 - LABX - VALID, Appel à projets générique - Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue - - TIMTAMDEN2014 - ANR-14-CE14-0029 - Appel à projets générique - VALID, Appel à projets générique - Multiplication et Relation avec l'hôte du virus Chikungunya - - CHIKV-Viro-Immuno2014 - ANR-14-CE14-0015 - Appel à projets générique - VALID
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Nature Communications
Nature Communications, Nature Publishing Group, 2021, 12 (1), pp.4354. ⟨10.1038/s41467-021-24521-x⟩
Nature Communications, 2021, 12 (1), pp.4354. ⟨10.1038/s41467-021-24521-x⟩
Nature Communications, Vol 12, Iss 1, Pp 1-16 (2021)
ISSN: 2041-1723
DOI: 10.1038/s41467-021-24521-x⟩
Popis: 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.
SARS-CoV-2 infection damages the airways. Here the authors show that SARS-CoV-2 infection induces the rapid loss of airway motile cilia, resulting in altered cilia clearance function. Cilia loss is preceded by reduced expression of the ciliogenesis regulator Foxj1.
Databáze: OpenAIRE
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