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.

KEYWORDS:

• Bronchiectasis
• P. aeruginosa
• airway acidification
• outer membrane vesicles
• type I interferonβ

Acknowledgements

We would like to express our sincere thanks to all the participants for their contributions to the study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability

The data generated in this study were available in the main text, the supplementary materials, the source data file were available after the article publication from [email protected] upon reasonable request.

Author contributions

Y Liu, YZ Xie, YH Shi and L Yang contributed equally to the work. JF Xu conceptualized and supervised the study, provided resources and acquired funding, interpreted the results, generated the figures, wrote and revised the manuscript. Y Liu recruited patients, performed experiments, analyzed results and generated figures, wrote the manuscript. YZ Xie, YH Shi and L Yang participated in the experiments, validated the results and revised the manuscript. XY Chen and LW Wang participated in data curation. JM Qu, D Weng and XJ Wang provided resources and revised the manuscript. HP Liu and BX Ge provided important input to the experimental design. JF Xu had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Additional information

Funding

This work was supported by the National Natural Science Fund for Distinguished Young Scholar (No. 81925001 to JF Xu), Key Scientific Innovation Project of Shanghai Municipal Education Commission (No. 202101070007-E00097 to JF Xu) and the Innovation Group Project of Shanghai Pulmonary Hospital to JF Xu. The National Natural Science Foundation of China (No. 31730025 to BX Ge).