Airway acidification impaired host defense against Pseudomonas aeruginosa infection by promoting type 1 interferon β response

Abstract

Airway microenvironment played an important role in the progression of chronic respiratory disease. Here we showed that standardized pondus hydrogenii (pH) of exhaled breath condensate (EBC) of bronchiectasis patients was significantly lower than that of controls and was significantly correlated with bronchiectasis severity index (BSI) scores and disease prognosis. EBC pH was lower in severe patients than that in mild and moderate patients. Besides, acidic microenvironment deteriorated Pseudomonas aeruginosa (P. aeruginosa) pulmonary infection in mice models. Mechanistically, acidic microenvironment increased P. aeruginosa outer membrane vesicles (PA_OMVs) released and boosted it induced the activation of interferon regulatory factor3 (IRF3)-interferonβ (IFN-β) signalling pathway, ultimately compromised the anti-bacteria immunity. Targeted knockout of IRF3 or type 1 interferon receptor (IFNAR1) alleviated lung damage and lethality of mice after P. aeruginosa infection that aggravated by acidic microenvironment. Together, these findings identified airway acidification impaired host resistance to P. aeruginosa infection by enhancing it induced the activation of IRF3-IFN-β signalling pathway. Standardized EBC pH may be a useful biomarker of disease severity and a potential therapeutic target for the refractory P. aeruginosa infection. The study also provided one more reference parameter for drug selection and new drug discovery for bronchiectasis.

How Does Airway Surface Liquid Composition Vary in Different Pulmonary Diseases, and How Can We Use This Knowledge to Model Microbial Infections?

“…ASL acidification also impairs S. aureus. clearance from human primary bronchial epithelial cells obtained from lobectomies [126] and P. aeruginosa clearance from a murine lung infection model [127]. Fungal pathogenesis is highly dependent upon pH, with many fungi, including Candida species and Aspergillus species able to utilise acidification and alkalinisation mechanisms to facilitate colonisation.…”

Combination Therapy with Ceftazidime-Avibactam and Amikacin for Multidrug-Resistant Pseudomonas aeruginosa Infection with Fulminant Myocarditis in a Younger Patient: A Case Report and Literature Review

“…Pseudomonas aeruginosa is a gram-negative bacterium widely distributed in nature and healthcare facilities. In hospitals, P. aeruginosa is often spread as an opportunistic pathogen to cause hospital-acquired infections (2). The infections are difficult to treat due to the complex mechanism of drug resistance (3).…”