Pseudomonas aeruginosa Modulates the Antiviral Response of Bronchial Epithelial Cells

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.

LasR-deficient Pseudomonas aeruginosa variants increase airway epithelial mICAM-1 expression and enhance neutrophilic lung inflammation

“…Our results also demonstrated that the enhanced mICAM-1 response was primarily attributable to the loss of LasR-regulated proteases that degraded ICAM-1, findings which are consistent with previous reports by our group and others that LasR-regulated proteases can degrade mediators of the innate immune system and the complement system [23,[46][47][48]54,69]. Furthermore, proteolytic cleavage of mICAM-1 by host-proteases such as neutrophil elastase and cathepsin G has been described [70,71], and degradation by bacterial proteases has been considered a potential mechanism of bacterial virulence [72].…”

“…LasR regulates the expression of several secreted proteases such as AprA, LasA, LasB and type IV protease (T4P) that can degrade components of host defenses and immunity [ 23 , 46 – 48 ], some of which have been shown to be heat-labile [ 23 , 49 ]. Therefore, we hypothesized that the loss of mICAM-1 protein signal upon stimulation with wild-type filtrates was due to the activity of these proteases, and sought to characterize the proteolytic activity in wild-type and lasR mutant filtrates.…”

“…Loss-of-function lasR mutants are common in chronic CF infections [13,52], and are associated with more severe lung disease [15] and increased markers of inflammation [23] in CF patients. They cause dysregulated bacterial-host interactions through multiple mechanisms [23,46,[53][54][55] that likely contribute to their propensity to cause greater pathology in chronic…”

“…Loss-of-function lasR mutants are common in chronic CF infections [ 13 , 52 ], and are associated with more severe lung disease [ 15 ] and increased markers of inflammation [ 23 ] in CF patients. They cause dysregulated bacterial-host interactions through multiple mechanisms [ 23 , 46 , 53 – 55 ] that likely contribute to their propensity to cause greater pathology in chronic infection. Our lab has previously shown that lasR mutant infections caused an increased pro-inflammatory cytokine and chemokine response in airway epithelial cells, and an exaggerated neutrophilic inflammation and lung immunopathology in vivo [ 23 ].…”

Pseudomonas aeruginosa Affects Airway Epithelial Response and Barrier Function During Rhinovirus Infection

“…These findings indicate that next to genetic differences, IL-6 degradation might also be affected by viral infection of the host cell. PA proteases have previously been described to also target CXCL-8 (LaFayette et al, 2015;Saint-Criq et al, 2018) and IFN-l (Sorensen et al, 2020). In our model, we found the effects of coinfection with PA and HRV16 on CXCL-8 to be similar to those of HRV infection alone.…”