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.
Subject(s)
COVID-19/pathology , Cilia/ultrastructure , Mucociliary Clearance/physiology , SARS-CoV-2 , Animals , Axoneme , Basal Bodies , Cilia/metabolism , Cilia/pathology , Cricetinae , Cytokines , Epithelial Cells/pathology , Forkhead Transcription Factors/metabolism , Humans , Lung/pathology , Male , Mesocricetus , Respiratory Mucosa/metabolism , Respiratory Mucosa/pathology , Virus ReplicationSubject(s)
Cilia/metabolism , Eye Diseases/metabolism , Flagella/metabolism , Heart Diseases/metabolism , Lung Diseases/metabolism , Polycystic Kidney Diseases/metabolism , Centrosome/metabolism , Centrosome/ultrastructure , Cilia/ultrastructure , Epithelial Cells/metabolism , Epithelial Cells/ultrastructure , Eye Diseases/genetics , Eye Diseases/pathology , Flagella/ultrastructure , Gene Expression Regulation , Heart Diseases/genetics , Heart Diseases/pathology , Hedgehog Proteins/genetics , Hedgehog Proteins/metabolism , Humans , Lung Diseases/genetics , Lung Diseases/pathology , Polycystic Kidney Diseases/genetics , Polycystic Kidney Diseases/pathology , Wnt Signaling PathwayABSTRACT
The novel coronavirus SARS-CoV-2 is the causative agent of the global coronavirus disease 2019 (COVID-19) outbreak. In addition to pneumonia, other COVID-19-associated symptoms have been reported, including loss of smell (anosmia). However, the connection between infection with coronavirus and anosmia remains enigmatic. It has been reported that defects in olfactory cilia lead to anosmia. In this Viewpoint, we summarize transmission electron microscopic studies of cilia in virus-infected cells. In the human nasal epithelium, coronavirus infects the ciliated cells and causes deciliation. Research has shown that viruses such as influenza and Sendai attach to the ciliary membrane. The Sendai virus enters cilia by fusing its viral membrane with the ciliary membrane. A recent study on SARS-CoV-2-human protein-protein interactions revealed that the viral nonstructural protein Nsp13 interacts with the centrosome components, providing a potential molecular link. The mucociliary escalator removes inhaled pathogenic particles and functions as the first line of protection mechanism against viral infection in the human airway. Thus, future investigation into the virus-cilium interface will help further the battle against COVID-19.