A recent study published in Cell Host & Microbe has provided novel insights into the persistence of bacterial infections in the lungs of individuals with cystic fibrosis (CF), even following treatment with advanced CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapies. The investigation involved targeted sampling of specific lung regions to characterize the spatial distribution and resilience of microbial colonization in response to treatment.
CF is a monogenic disorder caused by mutations in the CFTR gene, leading to defective ion transport across epithelial surfaces. This dysfunction results in the accumulation of thick, dehydrated mucus within the airways, creating an environment that promotes chronic bacterial infections. These infections contribute significantly to progressive airway inflammation, tissue damage, and respiratory decline. The introduction of CFTR modulator therapies has substantially improved lung function and overall quality of life by addressing the underlying molecular defect. Despite this, persistent infections within the lungs remain a major clinical challenge.
To investigate the basis of this persistence, researchers used bronchoscopic techniques to collect samples from different anatomical regions of the lung prior to the initiation of modulator therapy. The regions were selected to reflect varying degrees of infection, inflammation, and structural abnormalities. The same areas were sampled again one year after therapy to evaluate changes in microbial load and inflammatory markers.
The results revealed a complex and unexpected pattern. In patients who demonstrated microbiological clearance, lung inflammation was nearly absent after treatment, suggesting potential for long-term preservation of lung function. However, in patients with ongoing infections, bacteria and inflammation were detected throughout the lungs, including in areas without visible structural damage.
These findings challenge the prevailing view that persistent infection is primarily linked to irreversible tissue damage. Instead, they suggest that bacteria can survive in anatomically intact regions of the lung, indicating that structural compromise is not the sole determinant of infection persistence.
To explain this widespread colonization, the researchers proposed several possibilities. One is that bacteria from severely affected regions may disseminate into healthier areas. Alternatively, bacteria may undergo adaptive changes that allow them to evade immune defenses and persist despite the biochemical environment modified by modulator therapy, regardless of local tissue condition.
This study represents a significant advancement in understanding the regional dynamics of lung infections in CF. The approach of sampling defined areas within the lung offers greater detail than conventional methods such as sputum collection, which do not capture localized differences in infection and inflammation.
Supporting this evidence, a recent review by Jim Manos examined existing and emerging therapies targeting pulmonary infections in CF. The review highlighted that although CFTR modulators improve lung physiology and clinical outcomes, they do not eradicate chronic infections. This is largely attributed to the bacteria’s ability to form biofilms—dense aggregates that shield them from immune attack and antibiotic penetration. These biofilms allow bacterial populations to persist even in lung regions with minimal visible damage. Promising therapeutic innovations under development include bacteriophage therapy, inhibitors of quorum sensing, and agents that disrupt biofilm structure to enhance bacterial clearance.
Despite progress in therapy, critical questions remain. The exact mechanisms by which bacteria persist in lung regions that appear structurally preserved are not yet fully understood. Future research will aim to elucidate these processes, which may lead to the development of more precise and effective treatments for eradicating chronic infections in CF.
References
- Durfey SL, Kapnadak SG, Pena T, Willmering MM, Godwin JD, Teresi ME, et al. Pseudomonas infections persisting after CFTR modulators are widespread throughout the lungs and drive lung inflammation. Cell Host & Microbe [Internet]. 2025 Aug 5 [cited 2025 Aug 8]; Available from: https://www.sciencedirect.com/science/article/pii/S1931312825002811
- Manos J. Current and Emerging Therapies to Combat Cystic Fibrosis Lung Infections. Microorganisms. 2021 Sep 3;9(9):1874.