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Updated: Sep 12, 2025
Long Term Chronic Pseudomonas aeruginosa Airway Infection in Mice
Published on: March 17, 2014
Pseudomonas infections persisting after CFTR modulators are widespread throughout the lungs and drive lung
Samantha L Durfey1, Siddhartha G Kapnadak2, Tahuanty Pena3
1Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
Abstract:
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve the physiological defect causing cystic fibrosis, but the lungs of most people remain infected and inflamed. A leading hypothesis implicates damaged segments as the cause of persistent infection and predicts that mildly diseased segments within an individual's lungs will clear after treatment, whereas severely diseased segments will not. Our findings contradict this hypothesis. We used bronchoscopy to sample the least- and most-damaged lung segments in Pseudomonas aeruginosa (Pa)-infected individuals before modulators and returned to these same segments after 1.5 years. Surprisingly, we find an "all-or-none" infection clearance response: the most-diseased segments clear if any other lung segment in that person clears, and the least-diseased segments remain infected if others in that person do. Furthermore, neutrophilic inflammation completely resolves where Pa clears but remains elevated where Pa persists. These data indicate that post-modulator infections are not limited to severely diseased segments and that Pa infections drive persistent lung inflammation after modulators.
Insights
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators do not guarantee lung infection clearance. Pseudomonas aeruginosa infection clearance in any lung segment predicts clearance in others, regardless of disease severity.
Area of Science:
- Pulmonology
- Infectious Diseases
- Genetics
Background:
- Cystic fibrosis transmembrane conductance regulator (CFTR) modulators target the underlying defect in cystic fibrosis.
- Despite modulator treatment, persistent lung infections and inflammation remain a significant clinical challenge.
- Current hypotheses suggest localized disease severity dictates infection persistence post-treatment.
Purpose of the Study:
- To investigate the relationship between lung disease severity and Pseudomonas aeruginosa (Pa) infection clearance after CFTR modulator therapy.
- To determine if infection clearance is localized to specific lung segments based on initial disease severity.
- To assess the impact of Pa infection clearance on neutrophilic inflammation in different lung segments.
Main Methods:
- Longitudinal bronchoscopy with segmental sampling in individuals with cystic fibrosis and Pa infection before and after 1.5 years of CFTR modulator treatment.
- Comparison of Pa infection status and bacterial load in the least- and most-diseased lung segments.
- Quantification of neutrophilic inflammation markers in relation to infection clearance.
Main Results:
- An "all-or-none" pattern of infection clearance was observed across lung segments within individuals.
- Complete clearance of Pa infection in any lung segment correlated with clearance in all other segments, irrespective of initial disease severity.
- Neutrophilic inflammation resolved completely where Pa cleared but persisted where infection remained.
- Least-diseased segments did not necessarily clear infection if other segments remained infected.
Conclusions:
- Post-modulator infection clearance is not solely determined by the severity of disease in individual lung segments.
- The presence of Pseudomonas aeruginosa infection in any segment appears to drive persistent lung inflammation, even after CFTR modulator treatment.
- These findings challenge existing hypotheses and suggest a systemic or interconnected response to infection within the lungs.
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