SARS-CoV-2 induces transcriptional signatures in human lung epithelial cells that promote lung fibrosis.

Xu, J; Xu, X; Jiang, L; Dua, K; Hansbro, PM; Liu, G

SARS-CoV-2 induces transcriptional signatures in human lung epithelial cells that promote lung fibrosis.

Xu, J Xu, X

Jiang, L Dua, K

Hansbro, PM Liu, G

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Publisher:: BMC
Publication Type:: Journal Article
Citation:: Respiratory research, 2020, 21, (1)
Issue Date:: 2020-07-14

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Field	Value	Language
dc.contributor.author	Xu, J
dc.contributor.author	Xu, X https://orcid.org/0000-0003-4787-6547
dc.contributor.author	Jiang, L
dc.contributor.author	Dua, K https://orcid.org/0000-0002-7507-1159
dc.contributor.author	Hansbro, PM
dc.contributor.author	Liu, G https://orcid.org/0000-0002-0489-2638
dc.date.accessioned	2020-09-16T07:06:03Z
dc.date.available	2020-07-06
dc.date.available	2020-09-16T07:06:03Z
dc.date.issued	2020-07-14
dc.identifier.citation	Respiratory research, 2020, 21, (1)
dc.identifier.issn	1465-9921
dc.identifier.issn	1465-993X
dc.identifier.uri	http://hdl.handle.net/10453/142707
dc.description.abstract	BACKGROUND:Severe acute respiratory syndrome (SARS)-CoV-2-induced coronavirus disease-2019 (COVID-19) is a pandemic disease that affects > 2.8 million people worldwide, with numbers increasing dramatically daily. However, there is no specific treatment for COVID-19 and much remains unknown about this disease. Angiotensin-converting enzyme (ACE)2 is a cellular receptor of SARS-CoV-2. It is cleaved by type II transmembrane serine protease (TMPRSS)2 and disintegrin and metallopeptidase domain (ADAM)17 to assist viral entry into host cells. Clinically, SARS-CoV-2 infection may result in acute lung injury and lung fibrosis, but the underlying mechanisms of COVID-19 induced lung fibrosis are not fully understood. METHODS:The networks of ACE2 and its interacting molecules were identified using bioinformatic methods. Their gene and protein expressions were measured in human epithelial cells after 24 h SARS-CoV-2 infection, or in existing datasets of lung fibrosis patients. RESULTS:We confirmed the binding of SARS-CoV-2 and ACE2 by bioinformatic analysis. TMPRSS2, ADAM17, tissue inhibitor of metalloproteinase (TIMP)3, angiotensinogen (AGT), transformation growth factor beta (TGFB1), connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF) A and fibronectin (FN) were interacted with ACE2, and the mRNA and protein of these molecules were expressed in lung epithelial cells. SARS-CoV-2 infection increased ACE2, TGFB1, CTGF and FN1 mRNA that were drivers of lung fibrosis. These changes were also found in lung tissues from lung fibrosis patients. CONCLUSIONS:Therefore, SARS-CoV-2 binds with ACE2 and activates fibrosis-related genes and processes to induce lung fibrosis.
dc.format	Electronic
dc.language	eng
dc.publisher	BMC
dc.relation	http://purl.org/au-research/grants/nhmrc/1175134
dc.relation.ispartof	Respiratory research
dc.relation.isbasedon	10.1186/s12931-020-01445-6
dc.rights	info:eu-repo/semantics/restrictedAccess
dc.rights	© The Author(s). 2020Open AccessThis 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 giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visithttp://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata 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.mesh	Epithelial Cells
dc.subject.mesh	Humans
dc.subject.mesh	SARS Virus
dc.subject.mesh	Pneumonia, Viral
dc.subject.mesh	Coronavirus Infections
dc.subject.mesh	Pulmonary Fibrosis
dc.subject.mesh	Respiratory Distress Syndrome, Adult
dc.subject.mesh	Disease Progression
dc.subject.mesh	Peptidyl-Dipeptidase A
dc.subject.mesh	Receptors, Virus
dc.subject.mesh	Prevalence
dc.subject.mesh	Risk Assessment
dc.subject.mesh	Survival Analysis
dc.subject.mesh	Transcription, Genetic
dc.subject.mesh	Gene Expression Regulation
dc.subject.mesh	China
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Transcriptional Activation
dc.subject.mesh	Pandemics
dc.subject.mesh	Epithelial Cells
dc.subject.mesh	Humans
dc.subject.mesh	SARS Virus
dc.subject.mesh	Pneumonia, Viral
dc.subject.mesh	Coronavirus Infections
dc.subject.mesh	Pulmonary Fibrosis
dc.subject.mesh	Respiratory Distress Syndrome, Adult
dc.subject.mesh	Disease Progression
dc.subject.mesh	Peptidyl-Dipeptidase A
dc.subject.mesh	Receptors, Virus
dc.subject.mesh	Prevalence
dc.subject.mesh	Risk Assessment
dc.subject.mesh	Survival Analysis
dc.subject.mesh	Transcription, Genetic
dc.subject.mesh	Gene Expression Regulation
dc.subject.mesh	China
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Transcriptional Activation
dc.subject.mesh	Pandemics
dc.subject.mesh	China
dc.subject.mesh	Coronavirus Infections
dc.subject.mesh	Disease Progression
dc.subject.mesh	Epithelial Cells
dc.subject.mesh	Female
dc.subject.mesh	Gene Expression Regulation
dc.subject.mesh	Humans
dc.subject.mesh	Male
dc.subject.mesh	Pandemics
dc.subject.mesh	Peptidyl-Dipeptidase A
dc.subject.mesh	Pneumonia, Viral
dc.subject.mesh	Prevalence
dc.subject.mesh	Pulmonary Fibrosis
dc.subject.mesh	Receptors, Virus
dc.subject.mesh	Respiratory Distress Syndrome, Adult
dc.subject.mesh	Risk Assessment
dc.subject.mesh	SARS Virus
dc.subject.mesh	Survival Analysis
dc.subject.mesh	Transcription, Genetic
dc.subject.mesh	Transcriptional Activation
dc.title	SARS-CoV-2 induces transcriptional signatures in human lung epithelial cells that promote lung fibrosis.
dc.type	Journal Article
utslib.citation.volume	21
utslib.location.activity	England
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	1102 Cardiorespiratory Medicine and Haematology
utslib.for	1103 Clinical Sciences
utslib.for	1102 Cardiorespiratory Medicine and Haematology
utslib.for	1103 Clinical Sciences
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Graduate School of Health/GSH.Pharmacy
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Graduate School of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	recently_added	*
pubs.consider-herdc	false
dc.date.updated	2020-09-16T07:05:30Z
pubs.issue	1
pubs.publication-status	Published
pubs.volume	21
utslib.citation.issue	1

Abstract:

BACKGROUND:Severe acute respiratory syndrome (SARS)-CoV-2-induced coronavirus disease-2019 (COVID-19) is a pandemic disease that affects > 2.8 million people worldwide, with numbers increasing dramatically daily. However, there is no specific treatment for COVID-19 and much remains unknown about this disease. Angiotensin-converting enzyme (ACE)2 is a cellular receptor of SARS-CoV-2. It is cleaved by type II transmembrane serine protease (TMPRSS)2 and disintegrin and metallopeptidase domain (ADAM)17 to assist viral entry into host cells. Clinically, SARS-CoV-2 infection may result in acute lung injury and lung fibrosis, but the underlying mechanisms of COVID-19 induced lung fibrosis are not fully understood. METHODS:The networks of ACE2 and its interacting molecules were identified using bioinformatic methods. Their gene and protein expressions were measured in human epithelial cells after 24 h SARS-CoV-2 infection, or in existing datasets of lung fibrosis patients. RESULTS:We confirmed the binding of SARS-CoV-2 and ACE2 by bioinformatic analysis. TMPRSS2, ADAM17, tissue inhibitor of metalloproteinase (TIMP)3, angiotensinogen (AGT), transformation growth factor beta (TGFB1), connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF) A and fibronectin (FN) were interacted with ACE2, and the mRNA and protein of these molecules were expressed in lung epithelial cells. SARS-CoV-2 infection increased ACE2, TGFB1, CTGF and FN1 mRNA that were drivers of lung fibrosis. These changes were also found in lung tissues from lung fibrosis patients. CONCLUSIONS:Therefore, SARS-CoV-2 binds with ACE2 and activates fibrosis-related genes and processes to induce lung fibrosis.

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http://hdl.handle.net/10453/142707