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Virulent poxviruses inhibit DNA sensing by preventing STING activation

Georgana, Iliana, Sumner, Rebecca P., Towers, Greg J. and Maluquer de Motes, Carlos (2018) Virulent poxviruses inhibit DNA sensing by preventing STING activation Journal of Virology, 92 (10), e02145-17. e02145-17-1 - e02145-17-14.

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Abstract

Cytosolic recognition of DNA has emerged as a critical cellular mechanism of host immune activation upon pathogen invasion. The central cytosolic DNA sensor cGAS activates STING, which is phosphorylated, dimerises and translocates from the ER to a perinuclear region to mediate IRF-3 activation. Poxviruses are dsDNA viruses replicating in the cytosol and hence likely to trigger cytosolic DNA sensing. Here we investigated the activation of innate immune signalling by 4 different strains of the prototypic poxvirus vaccinia virus (VACV) in a cell line proficient in DNA sensing. Infection with the attenuated VACV strain MVA activated IRF-3 via cGAS and STING, and accordingly STING dimerised and was phosphorylated during MVA infection. Conversely, VACV strains Copenhagen and Western Reserve inhibited STING dimerisation and phosphorylation during infection and in response to transfected DNA and cGAMP, thus efficiently suppressing DNA sensing and IRF-3 activation. A VACV deletion mutant lacking protein C16, thought to be the only viral DNA sensing inhibitor acting upstream of STING, retained the ability to block STING activation. Similar inhibition of DNA-induced STING activation was also observed for cowpox and ectromelia viruses. Our data demonstrate that virulent poxviruses possess mechanisms for targeting DNA sensing at the level of the cGAS-STING axis and that these mechanisms do not operate in replication-defective strains such as MVA. These findings shed light on the role of cellular DNA sensing in poxvirus-host interactions and will open new avenues to determine its impact on VACV immunogenicity and virulence.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Georgana, Ilianai.georgana@surrey.ac.uk
Sumner, Rebecca P.
Towers, Greg J.
Maluquer de Motes, Carlosc.maluquerdemotes@surrey.ac.uk
Date : 28 February 2018
Funders : Biotechnology and Biological Sciences Research Council (BBSRC)
Identification Number : 10.1128/JVI.02145-17
Copyright Disclaimer : Copyright © 2018 Georgana et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Uncontrolled Keywords : DNA sensing; STING; Innate immunity; Poxvirus; Vaccinia virus
Depositing User : Clive Harris
Date Deposited : 23 Feb 2018 12:38
Last Modified : 18 May 2018 07:55
URI: http://epubs.surrey.ac.uk/id/eprint/845887

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