Abstract
Cystic fibrosis (CF) patients frequently acquire Pseudomonas aeruginosa infections that have been associated with a bad prognosis and an increased rate of pulmonary exacerbations. Respiratory viruses can cause exacerbations in chronic pulmonary diseases including COPD or asthma and have been suggested to contribute to exacerbations also in CF. In this study we investigated a possible link between P. aeruginosa infection and susceptibility to respiratory viruses. We show that P. aeruginosa is able to block the antiviral response of airway epithelial cells thereby promoting virus infection and spread. Mechanistically, P. aeruginosa secretes the protease AprA in a LasR dependent manner, which is able of directly degrading epithelial-derived IFNλ resulting in inhibition of IFN signaling. In addition, we correlate the virus infection status of CF patients with the ability of patients' P. aeruginosa isolates to degrade IFNλ. In line with this, the infection status of CF patients correlated significantly with the amount of respiratory viruses in sputum. Our data suggest that the interplay between P. aeruginosa and respiratory virus infections might partially explain the association of increased rates of pulmonary exacerbations and P. aeruginosa infections in CF patients.
Highlights
Cystic fibrosis (CF) is an autosomal recessive hereditary disease caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene
Cells treated with conditioned medium (CM) of P. aeruginosa strain PAO1 (CM-PAO1) showed a significant decrease in the induction of both genes after infection with human rhinoviruses (hRV) and respiratory syncytial virus (RSV), which was most pronounced after 14 h of infection compared to control medium [fold induction (FI) of MX1: 285 vs. 6, p < 0.001; FI OAS1: 49 vs. 1, p < 0.001; Figure 1A]
Viral infections have been linked to exacerbations in other chronic pulmonary diseases and respiratory virus infections in CF patients seem to be associated with higher viral burden and higher morbidity [29]
Summary
Cystic fibrosis (CF) is an autosomal recessive hereditary disease caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Mutations of CFTR lead to non- or mal-function of all exocrine glands and mucosal surfaces of the human body. The disease affects various organs including intestine, pancreas and lung [1]. Life expectancy of CF patients is severely decreased and this is nowadays mainly dictated by the pulmonary phenotype: CF patients suffer from thickened respiratory mucus causing mucus plugging of the airways, chronic inflammation as well as increased incidence of pulmonary bacterial infections. Infections are Pseudomonas aeruginosa Modulates Antiviral Responses of polymicrobial nature yet H. influenzae, S. aureus, and P. aeruginosa are clinically important pathogens in CF lung disease [2]. Bacterial airway infection and inflammation associated with reduced mucociliary clearance mediate progressive lung damage and a decline in lung function over time, resulting in death due to respiratory failure
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