Connexin-Dependent Transfer of cGAMP to Phagocytes Modulates Antiviral Responses
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
Affiliations
Geneviève Pépin
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
Dominic De Nardo
The Walter and Eliza Hall Institute of Medical Research, Inflammation Division, Parkville, Victoria, Australia
Christina L. Rootes
Australian Animal Health Laboratory, Commonwealth Scientific and Industrial Research Organisation (CSIRO) Health and Biosecurity, Geelong, Victoria, Australia
Tomalika R. Ullah
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
Sumaiah S. Al-Asmari
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
Katherine R. Balka
The Walter and Eliza Hall Institute of Medical Research, Inflammation Division, Parkville, Victoria, Australia
Hong-Mei Li
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
Kylie M. Quinn
Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
Fiona Moghaddas
The Walter and Eliza Hall Institute of Medical Research, Inflammation Division, Parkville, Victoria, Australia
Stephane Chappaz
Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
Benjamin T. Kile
Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
Eric F. Morand
School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
Seth L. Masters
The Walter and Eliza Hall Institute of Medical Research, Inflammation Division, Parkville, Victoria, Australia
Cameron R. Stewart
Australian Animal Health Laboratory, Commonwealth Scientific and Industrial Research Organisation (CSIRO) Health and Biosecurity, Geelong, Victoria, Australia
Bryan R. G. Williams
Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia
Michael P. Gantier
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
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.
