Copd-related modification to the airway epithelium permits intracellular residence of nontypeable haemophilus influenzae and may be potentiated by macrolide arrest of autophagy

Wee Peng Poh, Anthony Kicic, Susan E. Lester, Phan T. Nguyen, Lauren O. Bakaletz, Paul N. Reynolds, Sandra Hodge, Eugene Roscioli

Research output: Contribution to journalArticle

Abstract

Introduction: COPD is an inflammatory airway pathology associated with recurrent infection by nontypeable Haemophilus influenzae (NTHi) that is not effectively managed by macrolide antibiotic therapy. We hypothesised that NTHi is able to reside intracellularly within COPD-derived airway epithelial cells (AEC), and that the factors contained in cigarette smoke when coupled with exposure to erythromycin or azithromycin arrest autophagy, the principle mechanism responsible for clearing intracellular bacteria (called “xenophagy”). Methods: Cultures of bronchial airway epithelial cells derived from control and COPD participants were differentiated at an air–liquid interface and exposed to macrolide antibiotics, 10% cigarette smoke-extract (CSE) and NTHi. Markers of autophagic flux and intracellular NTHi were assessed using Western blot analysis and transmission electron microscopy. Results: AEC treated with macrolide antibiotics or 10% CSE exhibited a block in autophagic flux as evidenced by a concomitant increase in LC3-II and Sequestosome abundance (vs control; both P < 0.01). While control AEC showed no clear evidence of intracellular NTHi, COPDderived cultures exhibited abundant NTHi within the cytoplasm. Further, intracellular NTHi that were encapsulated within vesicles propagated from the apical epithelial layer to the basal cell layer. Discussion: Taken together, our findings indicate that COPD, cigarette smoke and macrolide antibiotics potentiate the susceptibility to persistent intracellular NTHi. A major mechanism for this is arresting normal autophagic flux in airway epithelial cells. Hence, structural modifications that mitigate this off-target effect of macrolides have significant potential to clear intracellular NTHi and thereby reduce the influence of this pathogen in the airways afflicted by COPD.

Original languageEnglish
Pages (from-to)1253-1260
Number of pages8
JournalInternational Journal of COPD
Volume15
DOIs
Publication statusPublished - 1 Jan 2020

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