NDLI: Acute cigarette smoke exposure leads to higher viral infection in human bronchial epithelial cultures by altering interferon, glycolysis and GDF15-related pathways

Content Provider	Springer Nature : BioMed Central
Author	Wang, Ying Ninaber, Dennis K. Faiz, Alen van der Linden, Abraham C. van Schadewijk, Annemarie Lutter, René Hiemstra, Pieter S. van der Does, Anne M. Ravi, Abilash
Abstract	Background Acute exacerbations of chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD), are frequently associated with rhinovirus (RV) infections. Despite these associations, the pathogenesis of virus-induced exacerbations is incompletely understood. We aimed to investigate effects of cigarette smoke (CS), a primary risk factor for COPD, on RV infection in airway epithelium and identify novel mechanisms related to these effects. Methods Primary bronchial epithelial cells (PBEC) from COPD patients and controls were differentiated by culture at the air–liquid interface (ALI) and exposed to CS and RV-A16. Bulk RNA sequencing was performed using samples collected at 6 and 24 h post infection (hpi), and viral load, mediator and l-lactate levels were measured at 6, 24 and 48hpi. To further delineate the effect of CS on RV-A16 infection, we performed growth differentiation factor 15 (GDF15) knockdown, l-lactate and interferon pre-treatment in ALI-PBEC. We performed deconvolution analysis to predict changes in the cell composition of ALI-PBEC after the various exposures. Finally, we compared transcriptional responses of ALI-PBEC to those in nasal epithelium after human RV-A16 challenge. Results CS exposure impaired antiviral responses at 6hpi and increased viral replication at 24 and 48hpi in ALI-PBEC. At 24hpi, CS exposure enhanced expression of RV-A16-induced epithelial interferons, inflammation-related genes and CXCL8. CS exposure increased expression of oxidative stress-related genes, of GDF15, and decreased mitochondrial membrane potential. GDF15 knockdown experiments suggested involvement of this pathway in the CS-induced increase in viral replication. Expression of glycolysis-related genes and l-lactate production were increased by CS exposure, and was demonstrated to contribute to higher viral replication. No major differences were demonstrated between COPD and non-COPD-derived cultures. However, cellular deconvolution analysis predicted higher secretory cells in COPD-derived cultures at baseline. Conclusion Altogether, our findings demonstrate that CS exposure leads to higher viral infection in human bronchial epithelium by altering not only interferon responses, but likely also through a switch to glycolysis, and via GDF15-related pathways.
Related Links	https://respiratory-research.biomedcentral.com/counter/pdf/10.1186/s12931-023-02511-5.pdf
Ending Page	16
Page Count	16
Starting Page	1
File Format	HTM / HTML
DOI	10.1186/s12931-023-02511-5
Journal	Respiratory Research
Issue Number	1
Volume Number	24
Language	English
Publisher	BioMed Central
Publisher Date	2023-08-23
Access Restriction	Open
Subject Keyword	Pneumology Respiratory System Bronchial epithelium Cigarette smoke Rhinovirus infection Chronic obstructive pulmonary disease (COPD) RNA-Seq Pneumology/Respiratory System
Content Type	Text
Resource Type	Article
Subject	Pulmonary and Respiratory Medicine
Journal Impact Factor	4.7/2023
5-Year Journal Impact Factor	5.3/2023

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