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

Respiratory Research

Research

René Lutter¹  Anne M. van der Does²  Annemarie van Schadewijk²  Ying Wang²  Pieter S. Hiemstra²  Abraham C. van der Linden²  Abilash Ravi²  Dennis K. Ninaber²  Alen Faiz³ 

[1] Department of Pulmonary Medicine, Amsterdam University Medical Center, University of Amsterdam, 1081HV, Amsterdam, The Netherlands;PulmoScience Lab, Department of Pulmonology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands;Respiratory Bioinformatics and Molecular Biology (RBMB), School of Life Sciences, University of Technology Sydney, 2007, Ultimo, Sydney, NSW, Australia;

关键词: Bronchial epithelium;    Cigarette smoke;    Rhinovirus infection;    Chronic obstructive pulmonary disease (COPD);    RNA-Seq;   

DOI  :  10.1186/s12931-023-02511-5

 received in 2023-05-04, accepted in 2023-08-13,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundAcute 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.MethodsPrimary 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.ResultsCS 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.ConclusionAltogether, 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.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

【 图 表 】

Fig. 2

Fig. 2

Fig. 3

13731_2023_311_Article_IEq7.gif

Fig. 1