Airway surface liquid antiviral activity in cystic fibrosis

Cystic fibrosis (CF) is a lethal genetic disease that affects 30,000 people in the United States alone. While the disease affects organs throughout the body, it is the lung disease that is the primary cause of morbidity and mortality for people with the disease. CF lung disease is characterized by thick and sticky mucus that obstructs the airways, acute and chronic bacterial infections, and chronic inflammation and remodeling. Thanks to the creation of the CF pig, it is now possible to study the manifestations of CF lung disease at birth. The CF pig develops spontaneous lung disease, similar to that found in humans with CF, making it the ideal model for our studies. One of the critical findings that revealed in studies of the CF pig is that airway surface liquid (ASL) bactericidal activity is impaired in CF at birth, and this activity is pH dependent. Because infants and children with CF tend to suffer greater morbidity from respiratory viruses than non-CF infants and children, we sought to determine if ASL has antiviral activity and if that activity is reduced in newborn CF pigs.

We found that pre-incubating either tracheal or nasal ASL from wild-type pigs reduced the infectivity of various recombinant viruses expressing an eGFP or GFP reporter gene. Those viruses include Sendai virus (SeV-eGFP), respiratory syncytial virus (RSV-GFP), the PR8 strain of influenza virus A (PR8-eGFP), and adenovirus (Ad-eGFP), indicating ASL has broad-spectrum antiviral activity. Nasal secretions from newborn CF pigs had strikingly reduced antiviral activity against SeV-eGFP and Ad-eGFP compared to nasal secretions from WT littermates. Unlike what was observed for ASL antibacterial activity, nasal secretion antiviral activity was not affected by pH, nor was it affected by bicarbonate concentration, one of the molecules that drives pH in the airways. However, when we mixed CF and WT nasal secretions at different ratios, we found the antiviral activity to follow a linear trend, with antiviral activity increasing as the percentage of WT nasal secretions increased. This suggests that one or more components of nasal secretions are found less abundantly in CF nasal secretions compared to WT nasal secretions, leading to reduced antiviral activity in CF. The CF pig has facilitated a much greater understanding of the early stages of CF lung disease. This model will allow us to determine what antiviral components are lacking in the CF airways and why they are reduced in CF.