COPD-Related Modification to the Airway Epithelium Permits Intracellular Residence of Nontypeable Haemophilus influenzae and May Be Potentiated by Macrolide Arrest of Autophagy
Bibliographic record
Abstract
Wee-Peng Poh,1 Anthony Kicic,1– 5 Susan E Lester,6 Phan T Nguyen,7,8 Lauren O Bakaletz,9 Paul N Reynolds,7,8 Sandra Hodge,7,8 Eugene Roscioli7,8 1Telethon Kids Institute, Centre for Health Research, The University of Western Australia, Nedlands 6009, Western Australia, Australia; 2Occupation and Environment, School of Public Health, Curtin University, Perth 6845, Western Australia, Australia; 3School of Biomedical Sciences, The University of Western Australia, Nedlands 6009, Western Australia, Australia; 4Department of Respiratory and Sleep Medicine, Perth Children’s Hospital, Nedlands 6009, Western Australia, Australia; 5Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, The University of Western Australia, Nedlands 6009, Western Australia, Australia; 6Department of Rheumatology, The Queen Elizabeth Hospital, Woodville, SA, Australia; 7Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, SA, Australia; 8Department of Medicine, The University of Adelaide, Adelaide, SA, Australia; 9Center for Microbial Pathogenesis, The Research Institute at Nationwide Children’s Hospital and the Ohio State University College of Medicine, Columbus, OH, USACorrespondence: Eugene RoscioliAdelaide Health and Medical Science Building, Corner of North Terrace and George St, Adelaide 5005, South Australia, AustraliaTel +61 8 8313 7088Email Eugene.Roscioli@adelaide.edu.auIntroduction: 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, COPD-derived 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.Keywords: antibiotic resistance, azithromycin, intracellular bacteria, macrolide, xenophagy
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".