Rhinovirus Load Is High despite Preserved Interferon-β Response in Cystic Fibrosis Bronchial Epithelial Cells

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.

Rhinovirus Infection Is Associated With Airway Epithelial Cell Necrosis and Inflammation via Interleukin-1 in Young Children With Cystic Fibrosis

“…The lack of apoptosis in CF AEC supports previous work in our laboratory where dampened apoptosis was observed following RV infection (8). This study supports data suggesting RV infection drives lytic cell death (7), potentially responsible for the increased viral load observed in CF (8,22).…”

“…Cleavage of the phosphatidylserine receptor by neutrophil elastase specifically disrupts phagocytosis of apoptotic cells (26,27) and as free neutrophil elastase is increased in the CF airway (28,29), it may explain the reduced apoptotic response and defective efferocytosis observed in the CF airway. Additionally, as suggested by the data in this study, a delayed apoptotic response following RV infection of AEC may also contribute to the defective apoptosis and increased viral load observed in CF (8,22). The study by Vandivier et al also found evidence of secondary necrosis following delayed apoptosis, potentially further exacerbating inflammation in the airway via release of DAMPs such as IL-1 signaling (26).…”

Pseudomonas aeruginosa Modulates the Antiviral Response of Bronchial Epithelial Cells

“…These findings indicate that most of the P. aeruginosa strains found in the environment and causing infections in CF patients are able to modulate the antiviral response since most of P. aeruginosa isolates are of group 1 or group 2. Two earlier studies could also demonstrate that P. aeruginosa is able to modulate the antiviral response of epithelial cells (31,32). In addition, the first study could demonstrate a difference in virus-induced IFN expression between healthy and CF-derived cells.…”

Progress in Model Systems of Cystic Fibrosis Mucosal Inflammation to Understand Aberrant Neutrophil Activity

“…In response to infection with respiratory viruses, studies have also observed increased IL-8 production in CF vs. non-CF pAEC (152,153), which is analogous to in vivo findings in pediatric CF patients with rhinovirus infection (154). However, other studies have reported no difference in inflammatory cytokine production as a result of in vitro viral infection (155,156). The filamentous fungi Aspergillus fumigatus is emerging as an important early life CF pathogen increasingly detected in pediatric CF airways (157,158), with A. fumigatus infection associated with increased air trapping among 5 year old CF patients (159).…”