Abstract
Lung disease in cystic fibrosis (CF) is often exacerbated following acute upper respiratory tract infections caused by the human rhinovirus (HRV). Pathophysiology of these exacerbations is presently unclear and may involve deficient innate antiviral or exaggerated inflammatory responses in CF airway epithelial cells. Furthermore, responses of CF cells to HRV may be adversely affected by pre-exposure to virulence factors of Pseudomonas (P.) aeruginosa, the microorganism that frequently colonizes CF airways. Here we examined production of antiviral cytokine interferon-β and inflammatory chemokine interleukin-8, expression of the interferon-responsive antiviral gene 2’-5’-oligoadenylate synthetase 1 (OAS1), and intracellular virus RNA load in primary CF (delF508 CFTR) and healthy airway epithelial cells following inoculation with HRV16. Parallel cells were exposed to virulence factors of P. aeruginosa prior to and during HRV16 inoculation. CF cells exhibited production of interferon-β and interleukin-8, and expression of OAS1 at levels comparable to those in healthy cells, yet significantly higher HRV16 RNA load during early hours post-inoculation with HRV16. In line with this, HRV16 RNA load was higher in the CFBE41o- dF cell line overexpessing delF508 CFTR, compared with the isogenic control CFBE41o- WT (wild-type CFTR). Pre-exposure to virulence factors of P. aeruginosa did not affect OAS1 expression or HRV16 RNA load, but potentiated interleukin-8 production. In conclusion, CF cells demonstrate elevated HRV RNA load despite preserved interferon-β and OAS1 responses. High HRV load in CF airway epithelial cells appears to be due to deficiencies manifesting early during HRV infection, and may not be related to interferon-β.
Highlights
Cystic fibrosis (CF) is a genetic multiorgan disease, in which infectious and inflammatory processes in the airways (CF lung disease) largely determine morbidity and premature demise
CF lung disease is often exacerbated following acute upper respiratory tract infections [1, 2], which are most commonly caused by human rhinoviruses (HRV) [1,2,3,4]
We first wished to compare IFN-β and IL-8 responses in healthy and CF HBE cells continuously inoculated with HRV16 (Fig 1A)
Summary
Cystic fibrosis (CF) is a genetic multiorgan disease, in which infectious and inflammatory processes in the airways (CF lung disease) largely determine morbidity and premature demise. HRV are positive-strand RNA viruses that replicate in airway epithelium of both upper and lower airways, causing innate antiviral responses. Central to these responses is production of interferon (IFN) -β, which up-regulates expression of interferon-responsive genes, such as 2’5’-oligoadenylate synthetase 1 (OAS1), that degrade viral nucleic acids, block translation of viral proteins, and attract immune cells to the airways. Antiviral immunity limits HRV infections to the upper airways of healthy individuals, but seems to be less efficient in CF, allowing the infection to spread to the lower airways This was demonstrated in exacerbated patients with CF whose lower airway secretions yielded high HRV load [5]
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