1. SARS-CoV-2 infection damages airway motile cilia and impairs mucociliary clearance
- Author
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Sylvain Levallois, Guillaume Duménil, Stéphane Rigaud, Françoise Lazarini, Olivier Gorgette, Lisa A. Chakrabarti, Rémy Robinot, Guilherme D. Melo, Julien Fernandes, Céline Trébeau, Pierre-Marie Lledo, Hervé Bourhy, Raphaël Etournay, Olivier Schwartz, Stacy Gellenoncourt, Samy Gobaa, Timothée Bruel, Florence Larrous, Mathieu Hubert, Marc Lecuit, Nikaïa Smith, Catherine Thouvenot, Darragh Duffy, Adeline Mallet, Vincent Michel, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Institut Pasteur [Paris] (IP), Perception et Mémoire / Perception and Memory, Immunologie Translationnelle - Translational Immunology lab, Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-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), Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Institut de l'Audition [Paris] (IDA), Plateforme technologique Biomatériaux et Microfluidique - Biomaterials and Microfluidics technologic Platform, Institut National de la Santé et de la Recherche Médicale (INSERM), Vaccine Research Institute [Créteil, France] (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), DIM ELICIT Region Ile-de-France, and ANRS (L.A.C.), the Vaccine Research Institute (ANR-10-LABX-77), ANRS, Labex IBEID (ANR-10-LABX-62-IBEID), 'TIMTAMDEN' ANR-14-CE14-0029, 'CHIKV-Viro-Immuno' ANR-14-CE14- 0015-01, the Gilead HIV cure program, ANR/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’s 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 French National Research Agency (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, Paris 7 University fellowship. S.L. is supported by FRM (fellowship ECO201906009119) and by 'Ecole Doctorale FIRE – Programme Bettencourt'., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(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), ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), ANR-20-COVI-0053,CoVarImm,Variation de la réponse immune systémique et muqueuse pendant l'infection par le SRAS-CoV-2 et la convalescence(2020), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaccine Research Institute (VRI), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
- Subjects
Axoneme ,0303 health sciences ,Tight junction ,Mucociliary clearance ,Cilium ,Biology ,respiratory system ,3. Good health ,Cell biology ,respiratory tract diseases ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Parenchyma ,Motile cilium ,medicine ,Basal body ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,030304 developmental biology ,Respiratory tract - Abstract
Understanding how SARS-CoV-2 spreads within the respiratory tract is important to define the parameters controlling the severity of COVID-19. We examined the functional and structural consequences of SARS-CoV-2 infection in a reconstituted human bronchial epithelium model. SARS-CoV-2 replication caused a transient decrease in epithelial barrier function and disruption of tight junctions, though viral particle crossing remained limited. Rather, SARS-CoV-2 replication led to a rapid loss of the ciliary layer, characterized at the ultrastructural level by axoneme loss and misorientation of remaining basal bodies. The motile cilia function was compromised, as measured in a mucociliary clearance assay. Epithelial defense mechanisms, including basal cell mobilization and interferon-lambda induction, ramped up only after the initiation of cilia damage. Analysis of SARS-CoV-2 infection in Syrian hamsters further demonstrated the loss of motile ciliain vivo. This study identifies cilia damage as a pathogenic mechanism that could facilitate SARS-CoV-2 spread to the deeper lung parenchyma.
- Published
- 2021