Cell type-specific roles of PAR1 in Coxsackievirus B3 infection

Abstract Protease-activated receptor 1 (PAR1) is widely expressed in humans and mice, and is activated by a variety of proteases, including thrombin. Recently, we showed that PAR1 contributes to the innate immune response to viral infection. Mice with a global deficiency of PAR1 expressed lower leve...

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Autores principales:	Michael F. Bode, Clare M. Schmedes, Grant J. Egnatz, Vanthana Bharathi, Yohei M. Hisada, David Martinez, Tomohiro Kawano, Alice Weithauser, Leah Rosenfeldt, Ursula Rauch, Joseph S. Palumbo, Silvio Antoniak, Nigel Mackman
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2196c66abee14dc480f8af601153009b
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spelling	oai:doaj.org-article:2196c66abee14dc480f8af601153009b2021-12-02T16:14:17ZCell type-specific roles of PAR1 in Coxsackievirus B3 infection10.1038/s41598-021-93759-82045-2322https://doaj.org/article/2196c66abee14dc480f8af601153009b2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93759-8https://doaj.org/toc/2045-2322Abstract Protease-activated receptor 1 (PAR1) is widely expressed in humans and mice, and is activated by a variety of proteases, including thrombin. Recently, we showed that PAR1 contributes to the innate immune response to viral infection. Mice with a global deficiency of PAR1 expressed lower levels of CXCL10 and had increased Coxsackievirus B3 (CVB3)-induced myocarditis compared with control mice. In this study, we determined the effect of cell type-specific deletion of PAR1 in cardiac myocytes (CMs) and cardiac fibroblasts (CFs) on CVB3-induced myocarditis. Mice lacking PAR1 in either CMs or CFs exhibited increased CVB3 genomes, inflammatory infiltrates, macrophages and inflammatory mediators in the heart and increased CVB3-induced myocarditis compared with wild-type controls. Interestingly, PAR1 enhanced poly I:C induction of CXCL10 in rat CFs but not in rat neonatal CMs. Importantly, activation of PAR1 reduced CVB3 replication in murine embryonic fibroblasts and murine embryonic cardiac myocytes. In addition, we showed that PAR1 reduced autophagy in murine embryonic fibroblasts and rat H9c2 cells, which may explain how PAR1 reduces CVB3 replication. These data suggest that PAR1 on CFs protects against CVB3-induced myocarditis by enhancing the anti-viral response whereas PAR1 on both CMs and fibroblasts inhibits viral replication.Michael F. BodeClare M. SchmedesGrant J. EgnatzVanthana BharathiYohei M. HisadaDavid MartinezTomohiro KawanoAlice WeithauserLeah RosenfeldtUrsula RauchJoseph S. PalumboSilvio AntoniakNigel MackmanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Michael F. Bode Clare M. Schmedes Grant J. Egnatz Vanthana Bharathi Yohei M. Hisada David Martinez Tomohiro Kawano Alice Weithauser Leah Rosenfeldt Ursula Rauch Joseph S. Palumbo Silvio Antoniak Nigel Mackman Cell type-specific roles of PAR1 in Coxsackievirus B3 infection
description	Abstract Protease-activated receptor 1 (PAR1) is widely expressed in humans and mice, and is activated by a variety of proteases, including thrombin. Recently, we showed that PAR1 contributes to the innate immune response to viral infection. Mice with a global deficiency of PAR1 expressed lower levels of CXCL10 and had increased Coxsackievirus B3 (CVB3)-induced myocarditis compared with control mice. In this study, we determined the effect of cell type-specific deletion of PAR1 in cardiac myocytes (CMs) and cardiac fibroblasts (CFs) on CVB3-induced myocarditis. Mice lacking PAR1 in either CMs or CFs exhibited increased CVB3 genomes, inflammatory infiltrates, macrophages and inflammatory mediators in the heart and increased CVB3-induced myocarditis compared with wild-type controls. Interestingly, PAR1 enhanced poly I:C induction of CXCL10 in rat CFs but not in rat neonatal CMs. Importantly, activation of PAR1 reduced CVB3 replication in murine embryonic fibroblasts and murine embryonic cardiac myocytes. In addition, we showed that PAR1 reduced autophagy in murine embryonic fibroblasts and rat H9c2 cells, which may explain how PAR1 reduces CVB3 replication. These data suggest that PAR1 on CFs protects against CVB3-induced myocarditis by enhancing the anti-viral response whereas PAR1 on both CMs and fibroblasts inhibits viral replication.
format	article
author	Michael F. Bode Clare M. Schmedes Grant J. Egnatz Vanthana Bharathi Yohei M. Hisada David Martinez Tomohiro Kawano Alice Weithauser Leah Rosenfeldt Ursula Rauch Joseph S. Palumbo Silvio Antoniak Nigel Mackman
author_facet	Michael F. Bode Clare M. Schmedes Grant J. Egnatz Vanthana Bharathi Yohei M. Hisada David Martinez Tomohiro Kawano Alice Weithauser Leah Rosenfeldt Ursula Rauch Joseph S. Palumbo Silvio Antoniak Nigel Mackman
author_sort	Michael F. Bode
title	Cell type-specific roles of PAR1 in Coxsackievirus B3 infection
title_short	Cell type-specific roles of PAR1 in Coxsackievirus B3 infection
title_full	Cell type-specific roles of PAR1 in Coxsackievirus B3 infection
title_fullStr	Cell type-specific roles of PAR1 in Coxsackievirus B3 infection
title_full_unstemmed	Cell type-specific roles of PAR1 in Coxsackievirus B3 infection
title_sort	cell type-specific roles of par1 in coxsackievirus b3 infection
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2196c66abee14dc480f8af601153009b
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Cell type-specific roles of PAR1 in Coxsackievirus B3 infection

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