Pleural Mesothelial Cells Modulate the Inflammatory/Profibrotic Response During SARS-CoV-2 Infection

Although lung fibrosis has a major impact in COVID-19 disease, its pathogenesis is incompletely understood. In particular, no direct evidence of pleura implication in COVID-19-related fibrotic damage has been reported so far. In this study, the expression of epithelial cytokeratins and Wilms tumor 1...

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Autores principales:	Giulia Matusali, Flavia Trionfetti, Veronica Bordoni, Roberta Nardacci, Laura Falasca, Daniele Colombo, Michela Terri, Claudia Montaldo, Concetta Castilletti, Davide Mariotti, Franca Del Nonno, Maria Rosaria Capobianchi, Chiara Agrati, Marco Tripodi, Raffaele Strippoli
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	SARS-CoV-2 mesothelial cells inflammatory cytokines pulmonary fibrosis mesothelial to mesenchymal transition WT1 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/975a667ac2d1474ea143ef2ac17ec492
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spelling	oai:doaj.org-article:975a667ac2d1474ea143ef2ac17ec4922021-12-01T07:31:38ZPleural Mesothelial Cells Modulate the Inflammatory/Profibrotic Response During SARS-CoV-2 Infection2296-889X10.3389/fmolb.2021.752616https://doaj.org/article/975a667ac2d1474ea143ef2ac17ec4922021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fmolb.2021.752616/fullhttps://doaj.org/toc/2296-889XAlthough lung fibrosis has a major impact in COVID-19 disease, its pathogenesis is incompletely understood. In particular, no direct evidence of pleura implication in COVID-19-related fibrotic damage has been reported so far. In this study, the expression of epithelial cytokeratins and Wilms tumor 1 (WT1), specific markers of mesothelial cells (MCs), was analyzed in COVID-19 and unrelated pleura autoptic samples. SARS-CoV-2 replication was analyzed by RT-PCR and confocal microscopy in MeT5A, a pleura MC line. SARS-CoV-2 receptors were analyzed by RT-PCR and western blot. Inflammatory cytokines from the supernatants of SARS-CoV-2-infected MeT5A cells were analysed by Luminex and ELLA assays. Immunohistochemistry of COVID-19 pleura patients highlighted disruption of pleura monolayer and fibrosis of the sub-mesothelial stroma, with the presence of MCs with fibroblastoid morphology in the sub-mesothelial stroma, but no evidence of direct infection in vivo. Interestingly, we found evidence of ACE2 expression in MCs from pleura of COVID-19 patients. In vitro analysis shown that MeT5A cells expressed ACE2, TMPRSS2, ADAM17 and NRP1, plasma membrane receptors implicated in SARS-CoV-2 cell entry and infectivity. Moreover, MeT5A cells sustained SARS-CoV-2 replication and productive infection. Infected MeT5A cells produced interferons, inflammatory cytokines and metalloproteases. Overall, our data highlight the potential role of pleura MCs as promoters of the fibrotic reaction and regulators of the immune response upon SARS-CoV-2 infection.Giulia MatusaliFlavia TrionfettiFlavia TrionfettiVeronica BordoniRoberta NardacciRoberta NardacciLaura FalascaDaniele ColomboMichela TerriMichela TerriClaudia MontaldoConcetta CastillettiDavide MariottiFranca Del NonnoMaria Rosaria CapobianchiChiara AgratiMarco TripodiMarco TripodiRaffaele StrippoliRaffaele StrippoliFrontiers Media S.A.articleSARS-CoV-2mesothelial cellsinflammatory cytokinespulmonary fibrosismesothelial to mesenchymal transitionWT1Biology (General)QH301-705.5ENFrontiers in Molecular Biosciences, Vol 8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	SARS-CoV-2 mesothelial cells inflammatory cytokines pulmonary fibrosis mesothelial to mesenchymal transition WT1 Biology (General) QH301-705.5
spellingShingle	SARS-CoV-2 mesothelial cells inflammatory cytokines pulmonary fibrosis mesothelial to mesenchymal transition WT1 Biology (General) QH301-705.5 Giulia Matusali Flavia Trionfetti Flavia Trionfetti Veronica Bordoni Roberta Nardacci Roberta Nardacci Laura Falasca Daniele Colombo Michela Terri Michela Terri Claudia Montaldo Concetta Castilletti Davide Mariotti Franca Del Nonno Maria Rosaria Capobianchi Chiara Agrati Marco Tripodi Marco Tripodi Raffaele Strippoli Raffaele Strippoli Pleural Mesothelial Cells Modulate the Inflammatory/Profibrotic Response During SARS-CoV-2 Infection
description	Although lung fibrosis has a major impact in COVID-19 disease, its pathogenesis is incompletely understood. In particular, no direct evidence of pleura implication in COVID-19-related fibrotic damage has been reported so far. In this study, the expression of epithelial cytokeratins and Wilms tumor 1 (WT1), specific markers of mesothelial cells (MCs), was analyzed in COVID-19 and unrelated pleura autoptic samples. SARS-CoV-2 replication was analyzed by RT-PCR and confocal microscopy in MeT5A, a pleura MC line. SARS-CoV-2 receptors were analyzed by RT-PCR and western blot. Inflammatory cytokines from the supernatants of SARS-CoV-2-infected MeT5A cells were analysed by Luminex and ELLA assays. Immunohistochemistry of COVID-19 pleura patients highlighted disruption of pleura monolayer and fibrosis of the sub-mesothelial stroma, with the presence of MCs with fibroblastoid morphology in the sub-mesothelial stroma, but no evidence of direct infection in vivo. Interestingly, we found evidence of ACE2 expression in MCs from pleura of COVID-19 patients. In vitro analysis shown that MeT5A cells expressed ACE2, TMPRSS2, ADAM17 and NRP1, plasma membrane receptors implicated in SARS-CoV-2 cell entry and infectivity. Moreover, MeT5A cells sustained SARS-CoV-2 replication and productive infection. Infected MeT5A cells produced interferons, inflammatory cytokines and metalloproteases. Overall, our data highlight the potential role of pleura MCs as promoters of the fibrotic reaction and regulators of the immune response upon SARS-CoV-2 infection.
format	article
author	Giulia Matusali Flavia Trionfetti Flavia Trionfetti Veronica Bordoni Roberta Nardacci Roberta Nardacci Laura Falasca Daniele Colombo Michela Terri Michela Terri Claudia Montaldo Concetta Castilletti Davide Mariotti Franca Del Nonno Maria Rosaria Capobianchi Chiara Agrati Marco Tripodi Marco Tripodi Raffaele Strippoli Raffaele Strippoli
author_facet	Giulia Matusali Flavia Trionfetti Flavia Trionfetti Veronica Bordoni Roberta Nardacci Roberta Nardacci Laura Falasca Daniele Colombo Michela Terri Michela Terri Claudia Montaldo Concetta Castilletti Davide Mariotti Franca Del Nonno Maria Rosaria Capobianchi Chiara Agrati Marco Tripodi Marco Tripodi Raffaele Strippoli Raffaele Strippoli
author_sort	Giulia Matusali
title	Pleural Mesothelial Cells Modulate the Inflammatory/Profibrotic Response During SARS-CoV-2 Infection
title_short	Pleural Mesothelial Cells Modulate the Inflammatory/Profibrotic Response During SARS-CoV-2 Infection
title_full	Pleural Mesothelial Cells Modulate the Inflammatory/Profibrotic Response During SARS-CoV-2 Infection
title_fullStr	Pleural Mesothelial Cells Modulate the Inflammatory/Profibrotic Response During SARS-CoV-2 Infection
title_full_unstemmed	Pleural Mesothelial Cells Modulate the Inflammatory/Profibrotic Response During SARS-CoV-2 Infection
title_sort	pleural mesothelial cells modulate the inflammatory/profibrotic response during sars-cov-2 infection
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/975a667ac2d1474ea143ef2ac17ec492
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Pleural Mesothelial Cells Modulate the Inflammatory/Profibrotic Response During SARS-CoV-2 Infection

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