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

Wang, Y; Ninaber, DK; Faiz, A; van der Linden, AC; van Schadewijk, A; Lutter, R; Hiemstra, PS; van der Does, AM; Ravi, A

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

Wang, Y Ninaber, DK Faiz, A

van der Linden, AC van Schadewijk, A Lutter, R Hiemstra, PS van der Does, AM Ravi, A

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Publisher:: Springer Nature
Publication Type:: Journal Article
Citation:: Respir Res, 2023, 24, (1), pp. 207
Issue Date:: 2023-08-23

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Field	Value	Language
dc.contributor.author	Wang, Y
dc.contributor.author	Ninaber, DK
dc.contributor.author	Faiz, A https://orcid.org/0000-0003-1740-3538
dc.contributor.author	van der Linden, AC
dc.contributor.author	van Schadewijk, A
dc.contributor.author	Lutter, R
dc.contributor.author	Hiemstra, PS
dc.contributor.author	van der Does, AM
dc.contributor.author	Ravi, A
dc.date.accessioned	2023-09-27T04:43:36Z
dc.date.available	2023-08-13
dc.date.available	2023-09-27T04:43:36Z
dc.date.issued	2023-08-23
dc.identifier.citation	Respir Res, 2023, 24, (1), pp. 207
dc.identifier.issn	1465-9921
dc.identifier.issn	1465-993X
dc.identifier.uri	http://hdl.handle.net/10453/172322
dc.description.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.
dc.format	Electronic
dc.language	eng
dc.publisher	Springer Nature
dc.relation	Maridulu Budyari Gumal - The Sydney Partnership for Health, Education, Research and Enterprise (SPHERE)RSEOH CAG SPHERE
dc.relation.ispartof	Respir Res
dc.relation.isbasedon	10.1186/s12931-023-02511-5
dc.rights	info:eu-repo/semantics/openAccess
dc.rights	© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
dc.subject	1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences
dc.subject.classification	Respiratory System
dc.subject.classification	3201 Cardiovascular medicine and haematology
dc.subject.classification	3202 Clinical sciences
dc.subject.mesh	Humans
dc.subject.mesh	Interferons
dc.subject.mesh	Growth Differentiation Factor 15
dc.subject.mesh	Cigarette Smoking
dc.subject.mesh	Virus Diseases
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Lactates
dc.subject.mesh	Humans
dc.subject.mesh	Virus Diseases
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Lactates
dc.subject.mesh	Interferons
dc.subject.mesh	Growth Differentiation Factor 15
dc.subject.mesh	Cigarette Smoking
dc.subject.mesh	Humans
dc.subject.mesh	Interferons
dc.subject.mesh	Growth Differentiation Factor 15
dc.subject.mesh	Cigarette Smoking
dc.subject.mesh	Virus Diseases
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Lactates
dc.title	Acute cigarette smoke exposure leads to higher viral infection in human bronchial epithelial cultures by altering interferon, glycolysis and GDF15-related pathways.
dc.type	Journal Article
utslib.citation.volume	24
utslib.location.activity	England
utslib.for	1102 Cardiorespiratory Medicine and Haematology
utslib.for	1103 Clinical Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
pubs.organisational-group	/University of Technology Sydney/Strength - CFI - Centre for Inflammation
utslib.copyright.status	open_access	*
dc.date.updated	2023-09-27T04:43:31Z
pubs.issue	1
pubs.publication-status	Published online
pubs.volume	24
utslib.citation.issue	1

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.

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