Abstract
BackgroundRespiratory viral infections are one of the main drivers of development and exacerbation for chronic airway inflammatory diseases. Increased viral susceptibility and impaired mucociliary clearance are often associated with chronic airway inflammatory diseases and served as risk factors of exacerbations. However, the links between viral susceptibility, viral clearance, and impaired mucociliary functions are unclear. Therefore, the objective of this study is to provide the insights into the effects of improper clearance of respiratory viruses from the epithelium following infection, and their resulting persistent activation of antiviral response, on mucociliary functions.MethodsIn order to investigate the effects of persistent antiviral responses triggered by viral components from improper clearance on cilia formation and function, we established an in vitro air–liquid interface (ALI) culture of human nasal epithelial cells (hNECs) and used Poly(I:C) as a surrogate of viral components to simulate their effects toward re-epithelization and mucociliary functions of the nasal epithelium following damages from a viral infection.ResultsThrough previous and current viral infection expression data, we found that respiratory viral infection of hNECs downregulated motile cilia gene expression. We then further tested the effects of antiviral response activation on the differentiation of hNECs using Poly(I:C) stimulation on differentiating human nasal epithelial stem/progenitor cells (hNESPCs). Using this model, we observed reduced ciliated cell differentiation compared to goblet cells, reduced protein and mRNA in ciliogenesis-associated markers, and increased mis-assembly and mis-localization of ciliary protein DNAH5 following treatment with 25 μg/ml Poly(I:C) in differentiating hNECs. Additionally, the cilia length and ciliary beat frequency (CBF) were also decreased, which suggest impairment of ciliary function as well.ConclusionOur results suggest that the impairments of ciliogenesis and ciliary function in hNECs may be triggered by specific expression of host antiviral response genes during re-epithelization of the nasal epithelium following viral infection. This event may in turn drive the development and exacerbation of chronic airway inflammatory diseases.
Highlights
The airway epithelial cells represent the primary line of defense against foreign materials entering the airway
As shown in our previous study, we observed a negative correlation between antiviral state activation and ciliary gene expression in chronic rhinosinusitis with nasal polyp (CRSwNP) patients (Peng et al, 2019b)
dynein axonemal heavy chain 5 (DNAH5), MCIDAS, and CCNO exhibited consistent descending trends in all infections tested, suggesting this observation to be applicable to multiple respiratory viruses (Figures 1A–C)
Summary
The airway epithelial cells represent the primary line of defense against foreign materials entering the airway. Respiratory viral infections are implicated as drivers and exacerbators of chronic airway inflammatory diseases (Tan et al, 2017, 2020) Respiratory viruses such as respiratory syncytial virus (RSV) directly affect the ciliary architecture and function (Smith et al, 2014), while influenza virus (IFV) and rhinovirus (RV) infections lead to the breakdown of the epithelial barrier (Tan et al, 2020). This results in viruses or viral components continuing to linger in the airway, constantly triggering pathogen sensors and antiviral immunity (Marin et al, 2000; Kling et al, 2005; Wood et al, 2011) Such constant activation of antiviral immune response can potentially affect the re-epithelization following infection, driving the pathogenesis and exacerbation of chronic airway inflammatory diseases (Cho et al, 2013; Ravi et al, 2019). The objective of this study is to provide the insights into the effects of improper clearance of respiratory viruses from the epithelium following infection, and their resulting persistent activation of antiviral response, on mucociliary functions
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