Rhinovirus infection promotes suppression of sphingosine and enhanced bacterial infection in cystic fibrosis airways.

Viral infections often sensitize, via unknown molecular mechanisms, the respiratory tract to bacterial infections or induce severe exacerbations in cystic fibrosis (CF). CF, which is caused by inactivation of Cftr, affects approximately 80,000 individuals in the United States and Western Europe. Currently, pulmonary complications drive morbidity and mortality for patients with CF, while gastrointestinal problems associated with CF are relatively well-controlled. Here we identify in mouse tracheae and human lung tissue a constitutive upregulation of Stat3 in CFTR/Cftr-deficient cells. This results in activation of interferon regulatory factor 8 (IRF8) and a downregulation of acid ceramidase activity and cellular sphingosine levels. Infection of mouse tracheae with rhinovirus (RV) strains 1B or 2 markedly enhanced these changes in Cftr-deficient cells. Rhinovirus infections also induced Stat3 activation, upregulation of IRF8 expression, down-regulation of acid ceramidase activity and sphingosine levels in airway epithelial cells from wildtype mice, although to a lower level than in CF cells. Inhibition of Stat3 prevented the constitutive and rhinoviral-induced upregulation of IRF8 in CF tracheal epithelial cells and restored acid ceramidase activity and sphingosine levels in these cells to almost normal values. Upregulation of sphingosine in Cftr-deficient epithelial cells by Stat3 inhibition or reconstitution of sphingosine levels by treatment with exogenous sphingosine restored resistance of tracheal epithelial cells to Pseudomonas aeruginosa infections. The data suggest that rhinoviral infections facilitate bacterial infections of airway epithelial cells by a cascade consisting of Stat3 activation, IRF8 upregulation, downregulation of acid ceramidase activity, and reduced sphingosine levels.