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Cathepsin B, Airway Pathogens, and Inflammation in the Lower Airways of Children With Cystic Fibrosis

Matthew K Fought¹, John B O'Connor², Brandie D Wagner³

¹Division of Pulmonary and Sleep Medicine, University of Washington and Seattle Children's Hospital, Seattle, Washington, USA.

Pediatric Pulmonology

|August 14, 2026

Insights

Cathepsin B (CTSB) levels are elevated in cystic fibrosis (CF) airways, correlating with bacterial and fungal infections and inflammation. CTSB may serve as a biomarker for infection-related lung disease in CF patients.

Area of Science:

Pulmonary Medicine
Biochemistry
Microbiology

Background:

Protease dysregulation is implicated in cystic fibrosis (CF) airway inflammation and remodeling.
The specific role of lysosomal cysteine protease Cathepsin B (CTSB) in CF pathogenesis is not fully understood.

Purpose of the Study:

To investigate the relationship between pro-CTSB and mature CTSB activity with CF-specific pathogens and airway inflammation in children.
To determine if CTSB levels can serve as a biomarker in CF.

Main Methods:

Bronchoalveolar lavage fluid (BALF) was analyzed from children with and without CF.
CTSB levels (pro- and mature) were measured using ELISA, activity assays, and Western blot.
Bacterial and fungal loads and community composition were quantified.
Proinflammatory cytokines and neutrophil elastase (NE) were measured.

Main Results:

Pro-CTSB and CTSB activity were significantly higher in CF BALF, particularly with Staphylococcus aureus presence.
CTSB levels correlated with specific pathogen loads (Staphylococcus aureus, Aspergillus spp.), reduced bacterial diversity, and increased total fungal load.
Both CTSB measures strongly correlated with NE and proinflammatory cytokines.
Pro-CTSB concentrations showed a negative correlation with FEV1/FVC in CF patients.

Conclusions:

BALF CTSB concentration may indicate infection-related inflammation in CF.
CTSB may serve as a CF-specific biomarker for obstructive lung disease linked to pathogen interactions.

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Abstract

Introduction:

Dysregulated protease activity contributes to airway inflammation and tissue remodeling in cystic fibrosis (CF); however, the role of the lysosomal cysteine protease Cathepsin B (CTSB) remains incompletely defined. This cross-sectional study investigates relationships between pro-CTSB and mature CTSB activity with CF-specific pathogens and airway inflammation in children with and without CF.

Methods:

Bronchoalveolar lavage fluid (BALF) was collected from clinically indicated bronchoscopies in children (N = 52 CF, N = 161 non-CF). CTSB was interrogated using ELISA, fluorogenic activity assay, and Western blot analysis to distinguish pro- and mature CTSB. Total bacterial and total fungal load (TFL) were quantified by quantitative polymerase chain reaction, and community composition was determined by 16S bacterial and 18S fungal sequencing. Concentrations of proinflammatory cytokines and neutrophil elastase (NE) were measured via Luminex multiplatform and a spectrophotometric assay, respectively. Analyses included Spearman's rank correlations and Wilcoxon rank-based tests.

Results:

Pro-CTSB and CTSB activity were significantly (p < 0.01) elevated in CF BALF and in samples with a positive Staphylococcus aureus airway culture. Pro-CTSB concentrations correlated with staphylococcal relative abundance (RA, $ρ$ = 0.25, p < 0.02) and reduced bacterial diversity ( $ρ$ = -0.41, p < 0.01). Mature CTSB activity correlated with TFL ( $ρ$ = 0.50, p < 0.05) and Aspergillus spp. RA ( $ρ$ = 0.36, p < 0.04). Western blot analysis confirmed pro-CTSB expression and mature CTSB in BALF with measurable activity. Both CTSB measures correlated strongly with NE and proinflammatory cytokines ( $ρ$ ≥ 0.47, p < 0.001). Pro-CTSB concentrations negatively correlated with FEV1/FVC measurements in CF ( $ρ$ = -0.32, p = 0.05).

Conclusions:

BALF CTSB concentration may serve as a CF-specific biomarker of infection-related inflammation and obstructive lung disease driven by specific pathogen interactions.

Keywords:

Staphylococcus aureus cathepsin B cystic fibrosis cytokine inflammation microbiome mycobiome neutrophil elastase

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