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Viral cGAMP nuclease reveals the essential role of DNA sensing in protection against acute lethal virus infection

Hernáez, Bruno, Alonso, Graciela, Georgana, Iliana, El-Jesr, Misbah, Martín, Rocío, Shair, Kathy H. Y., Fischer, Cornelius, Sauer, Sascha, Maluquer de Motes, Carlos and Alcamí, Antonio (2020) Viral cGAMP nuclease reveals the essential role of DNA sensing in protection against acute lethal virus infection Science Advances.

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Abstract

Cells contain numerous immune sensors to detect virus infection. The cyclic GMP-AMP (cGAMP) synthase (cGAS) recognizes cytosolic DNA and activates innate immune responses via stimulator 2of interferon genes (STING), but the impact of DNA sensing pathways on host protective responses has not been fully defined. We demonstrate that cGAS/STING activation is required to resist lethal poxvirus infection. We identified viral Schlafen (vSlfn) as the main STING inhibitor and ectromelia virus was severely attenuated in the absence of vSlfn. Both vSlfn-mediated virulence and STING inhibitory activity mapped to the recently discovered poxin cGAMP nuclease domain. Animals were protected from subcutaneous, respiratory and intravenous infection in the absence of vSlfn, and interferon was the main anti-viral protective mechanism controlled by the DNA sensing pathway. Our findings support that manipulation of DNA sensing is an efficient therapeutic strategy in diseases triggered by viral infection or tissue damage-mediated release of self-DNA.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Hernáez, Bruno
Alonso, Graciela
Georgana, Ilianai.georgana@surrey.ac.uk
El-Jesr, Misbah
Martín, Rocío
Shair, Kathy H. Y.
Fischer, Cornelius
Sauer, Sascha
Maluquer de Motes, Carlosc.maluquerdemotes@surrey.ac.uk
Alcamí, Antonio
Date : 2020
Funders : European Union Seventh Framework Programme, Wellcome Trust, Biotechnology and Biological Sciences Research Council (BBSRC)
Grant Title : European Sequencing and Genotyping Infrastructure
Copyright Disclaimer : Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
Related URLs :
Depositing User : Clive Harris
Date Deposited : 17 Aug 2020 14:37
Last Modified : 17 Aug 2020 14:37
URI: http://epubs.surrey.ac.uk/id/eprint/858419

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