Connexin-Dependent Transfer of cGAMP to Phagocytes Modulates Antiviral Responses

ABSTRACT Activation of cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in antiviral responses to many DNA viruses. Sensing of cytosolic DNA by cGAS results in synthesis of the endogenous second messenger cGAMP that activates stimulator of interferon genes (STING) in infected cells. Crit...

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Autores principales:	Geneviève Pépin, Dominic De Nardo, Christina L. Rootes, Tomalika R. Ullah, Sumaiah S. Al-Asmari, Katherine R. Balka, Hong-Mei Li, Kylie M. Quinn, Fiona Moghaddas, Stephane Chappaz, Benjamin T. Kile, Eric F. Morand, Seth L. Masters, Cameron R. Stewart, Bryan R. G. Williams, Michael P. Gantier
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	connexins STING cGAMP cGAS Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/cbfc430aefe94522b1b1208699100db7
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spelling	oai:doaj.org-article:cbfc430aefe94522b1b1208699100db72021-11-15T15:56:58ZConnexin-Dependent Transfer of cGAMP to Phagocytes Modulates Antiviral Responses10.1128/mBio.03187-192150-7511https://doaj.org/article/cbfc430aefe94522b1b1208699100db72020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03187-19https://doaj.org/toc/2150-7511ABSTRACT Activation of cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in antiviral responses to many DNA viruses. Sensing of cytosolic DNA by cGAS results in synthesis of the endogenous second messenger cGAMP that activates stimulator of interferon genes (STING) in infected cells. Critically, cGAMP can also propagate antiviral responses to uninfected cells through intercellular transfer, although the modalities of this transfer between epithelial and immune cells remain poorly defined. We demonstrate here that cGAMP-producing epithelial cells can transactivate STING in cocultured macrophages through direct cGAMP transfer. cGAMP transfer was reliant upon connexin expression by epithelial cells and pharmacological inhibition of connexins blunted STING-dependent transactivation of the macrophage compartment. Macrophage transactivation by cGAMP contributed to a positive-feedback loop amplifying antiviral responses, significantly protecting uninfected epithelial cells against viral infection. Collectively, our findings constitute the first direct evidence of a connexin-dependent cGAMP transfer to macrophages by epithelial cells, to amplify antiviral responses. IMPORTANCE Recent studies suggest that extracellular cGAMP can be taken up by macrophages to engage STING through several mechanisms. Our work demonstrates that connexin-dependent communication between epithelial cells and macrophages plays a significant role in the amplification of antiviral responses mediated by cGAMP and suggests that pharmacological strategies aimed at modulating connexins may have therapeutic applications to control antiviral responses in humans.Geneviève PépinDominic De NardoChristina L. RootesTomalika R. UllahSumaiah S. Al-AsmariKatherine R. BalkaHong-Mei LiKylie M. QuinnFiona MoghaddasStephane ChappazBenjamin T. KileEric F. MorandSeth L. MastersCameron R. StewartBryan R. G. WilliamsMichael P. GantierAmerican Society for MicrobiologyarticleconnexinsSTINGcGAMPcGASMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	connexins STING cGAMP cGAS Microbiology QR1-502
spellingShingle	connexins STING cGAMP cGAS Microbiology QR1-502 Geneviève Pépin Dominic De Nardo Christina L. Rootes Tomalika R. Ullah Sumaiah S. Al-Asmari Katherine R. Balka Hong-Mei Li Kylie M. Quinn Fiona Moghaddas Stephane Chappaz Benjamin T. Kile Eric F. Morand Seth L. Masters Cameron R. Stewart Bryan R. G. Williams Michael P. Gantier Connexin-Dependent Transfer of cGAMP to Phagocytes Modulates Antiviral Responses
description	ABSTRACT Activation of cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in antiviral responses to many DNA viruses. Sensing of cytosolic DNA by cGAS results in synthesis of the endogenous second messenger cGAMP that activates stimulator of interferon genes (STING) in infected cells. Critically, cGAMP can also propagate antiviral responses to uninfected cells through intercellular transfer, although the modalities of this transfer between epithelial and immune cells remain poorly defined. We demonstrate here that cGAMP-producing epithelial cells can transactivate STING in cocultured macrophages through direct cGAMP transfer. cGAMP transfer was reliant upon connexin expression by epithelial cells and pharmacological inhibition of connexins blunted STING-dependent transactivation of the macrophage compartment. Macrophage transactivation by cGAMP contributed to a positive-feedback loop amplifying antiviral responses, significantly protecting uninfected epithelial cells against viral infection. Collectively, our findings constitute the first direct evidence of a connexin-dependent cGAMP transfer to macrophages by epithelial cells, to amplify antiviral responses. IMPORTANCE Recent studies suggest that extracellular cGAMP can be taken up by macrophages to engage STING through several mechanisms. Our work demonstrates that connexin-dependent communication between epithelial cells and macrophages plays a significant role in the amplification of antiviral responses mediated by cGAMP and suggests that pharmacological strategies aimed at modulating connexins may have therapeutic applications to control antiviral responses in humans.
format	article
author	Geneviève Pépin Dominic De Nardo Christina L. Rootes Tomalika R. Ullah Sumaiah S. Al-Asmari Katherine R. Balka Hong-Mei Li Kylie M. Quinn Fiona Moghaddas Stephane Chappaz Benjamin T. Kile Eric F. Morand Seth L. Masters Cameron R. Stewart Bryan R. G. Williams Michael P. Gantier
author_facet	Geneviève Pépin Dominic De Nardo Christina L. Rootes Tomalika R. Ullah Sumaiah S. Al-Asmari Katherine R. Balka Hong-Mei Li Kylie M. Quinn Fiona Moghaddas Stephane Chappaz Benjamin T. Kile Eric F. Morand Seth L. Masters Cameron R. Stewart Bryan R. G. Williams Michael P. Gantier
author_sort	Geneviève Pépin
title	Connexin-Dependent Transfer of cGAMP to Phagocytes Modulates Antiviral Responses
title_short	Connexin-Dependent Transfer of cGAMP to Phagocytes Modulates Antiviral Responses
title_full	Connexin-Dependent Transfer of cGAMP to Phagocytes Modulates Antiviral Responses
title_fullStr	Connexin-Dependent Transfer of cGAMP to Phagocytes Modulates Antiviral Responses
title_full_unstemmed	Connexin-Dependent Transfer of cGAMP to Phagocytes Modulates Antiviral Responses
title_sort	connexin-dependent transfer of cgamp to phagocytes modulates antiviral responses
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/cbfc430aefe94522b1b1208699100db7
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Connexin-Dependent Transfer of cGAMP to Phagocytes Modulates Antiviral Responses

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