SARS-CoV-2 particles promote airway epithelial differentiation and ciliation

Julian Gonzalez-Rubio; Vu Thuy Khanh Le-Trilling; Lea Baumann; Maria Cheremkhina; Hannah Kubiza; Anja E Luengen; Sebastian Reuter; Christian Taube; Stephan Ruetten; Daniela Duarte Campos; Christian G Cornelissen; Mirko Trilling; Anja Lena Thiebes

doi:10.3389/fbioe.2023.1268782

SARS-CoV-2 particles promote airway epithelial differentiation and ciliation

Front Bioeng Biotechnol. 2023 Nov 2:11:1268782. doi: 10.3389/fbioe.2023.1268782. eCollection 2023.

Authors

Affiliations

¹ Department of Biohybrid and Medical Textiles (BioTex), AME-Institute of Applied Medical Engineering, Helmholtz Institute, RWTH Aachen University, Aachen, Germany.
² Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
³ Department of Pulmonary Medicine, University Medical Center Essen-Ruhrlandklinik, Essen, Germany.
⁴ Institute of Pathology, Electron Microscopy Facility, RWTH Aachen University Hospital, Aachen, Germany.
⁵ Bioprinting and Tissue Engineering Group, Center for Molecular Biology of Heidelberg University (ZMBH), Heidelberg, Germany.
⁶ Clinic for Pneumology and Internal Intensive Care Medicine (Medical Clinic V), RWTH Aachen University Hospital, Aachen, Germany.

Abstract

Introduction: The Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which caused the coronavirus disease 2019 (COVID-19) pandemic, enters the human body via the epithelial cells of the airway tract. To trap and eject pathogens, the airway epithelium is composed of ciliated and secretory cells that produce mucus which is expelled through a process called mucociliary clearance. Methods: This study examines the early stages of contact between SARS-CoV-2 particles and the respiratory epithelium, utilizing 3D airway tri-culture models exposed to ultraviolet light-irradiated virus particles. These cultures are composed of human endothelial cells and human tracheal mesenchymal cells in a fibrin hydrogel matrix covered by mucociliated human tracheal epithelial cells. Results: We found that SARS-CoV-2 particles trigger a significant increase in ciliation on the epithelial surface instructed through a differentiation of club cells and basal stem cells. The contact with SARS-CoV-2 particles also provoked a loss of cell-cell tight junctions and impaired the barrier integrity. Further immunofluorescence analyses revealed an increase in FOXJ1 expression and PAK1/2 phosphorylation associated with particle-induced ciliation. Discussion: An understanding of epithelial responses to virus particles may be instrumental to prevent or treat respiratory infectious diseases such as COVID-19.

Keywords: COVID-19; SARS-CoV-2; airway tissue engineering; cilia; differentiation; epithelial cells; lung innate immunity; stem cells.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The study was supported by the Volkswagen Foundation (Grant No. Az 99078) and the German Research Foundation (DFG, Grant No. 496706372, TH2522/2-1, Grant No. 495328185).