Abstract
Early-life viral infections are responsible for pulmonary exacerbations that can contribute to disease progression in young children with cystic fibrosis (CF). The most common respiratory viruses detected in the CF airway are human rhinoviruses (RV), and augmented airway inflammation in CF has been attributed to dysregulated airway epithelial responses although evidence has been conflicting. Here, we exposed airway epithelial cells from children with and without CF to RV in vitro. Using RNA-Seq, we profiled the transcriptomic differences of CF and non-CF airway epithelial cells at baseline and in response to RV. There were only modest differences between CF and non-CF cells at baseline. In response to RV, there were 1,442 and 896 differentially expressed genes in CF and non-CF airway epithelial cells, respectively. The core antiviral responses in CF and non-CF airway epithelial cells were mediated through interferon signaling although type 1 and 3 interferon signaling, when measured, were reduced in CF airway epithelial cells following viral challenge consistent with previous reports. The transcriptional responses in CF airway epithelial cells were more complex than in non-CF airway epithelial cells with diverse over-represented biological pathways, such as cytokine signaling and metabolic and biosynthetic pathways. Network analysis highlighted that the differentially expressed genes of CF airway epithelial cells' transcriptional responses were highly interconnected and formed a more complex network than observed in non-CF airway epithelial cells. We corroborate observations in fully differentiated air–liquid interface (ALI) cultures, identifying genes involved in IL-1 signaling and mucin glycosylation that are only dysregulated in the CF airway epithelial response to RV infection. These data provide novel insights into the CF airway epithelial cells' responses to RV infection and highlight potential pathways that could be targeted to improve antiviral and anti-inflammatory responses in CF.
Highlights
Lung disease is the major cause of morbidity and mortality in cystic fibrosis (CF) [1]
To improve knowledge of the underlying epithelial transcriptional responses during infection with rhinovirus, a major respiratory pathogen, we performed RNA sequencing on primary airway epithelial cells (AEC) from children with CF and non-CF controls in vitro at baseline and post-RV infection
AIM2 inflammasome [51, 52] IFI27 contributes to IFN-dependent perturbation of normal mitochondrial function and enhanced cellular apoptosis [53], and the IFN-dependent antiviral factor BST2 were all significantly downregulated in CF AECs
Summary
Lung disease is the major cause of morbidity and mortality in cystic fibrosis (CF) [1]. Intermittent pulmonary exacerbations occur in individuals with CF who experience increased respiratory symptoms and reduction in pulmonary function that are responsive to therapy with antibiotics [7]. The frequency of exacerbations is a predictor of long-term morbidity and irreversible loss of lung function [8, 9]. The triggers for these pulmonary exacerbations are not fully understood it is recognized that lower respiratory infections caused by viruses are likely to play a significant role [10,11,12,13,14]. The nature of any intrinsic deficiency still remains unclear some explanations are emerging [25]
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