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Persistent innate immune stimulation results in IRF3-mediated but caspase-independent cytostasis

Persistent virus infection continuously produces non-self nucleic acids that activate cell-intrinsic immune responses. However, the antiviral defense evolved as a transient, acute phase response and the effects of persistently ongoing stimulation onto cellular homeostasis are not well understood. To...

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Main Authors: Urban, Christian (Author) , Welsch, Hendrik (Author) , Heine, Katharina (Author) , Wüst, Sandra (Author) , Haas, Darya A. (Author) , Dächert, Christopher (Author) , Pandey, Aparna (Author) , Pichlmair, Andreas (Author) , Binder, Marco (Author)
Format: Article (Journal)
Language:English
Published: 11 June 2020
In: Viruses
Year: 2020, Volume: 12, Issue: 6
ISSN:1999-4915
DOI:10.3390/v12060635
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/v12060635
Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/1999-4915/12/6/635
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Author Notes:Christian Urban, Hendrik Welsch, Katharina Heine, Sandra Wüst, Darya A. Haas, Christopher Dächert, Aparna Pandey, Andreas Pichlmair and Marco Binder

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520 |a Persistent virus infection continuously produces non-self nucleic acids that activate cell-intrinsic immune responses. However, the antiviral defense evolved as a transient, acute phase response and the effects of persistently ongoing stimulation onto cellular homeostasis are not well understood. To study the consequences of long-term innate immune activation, we expressed the NS5B polymerase of Hepatitis C virus (HCV), which in absence of viral genomes continuously produces immune-stimulatory RNAs. Surprisingly, within 3 weeks, NS5B expression declined and the innate immune response ceased. Proteomics and functional analyses indicated a reduced proliferation of those cells most strongly stimulated, which was independent of interferon signaling but required mitochondrial antiviral signaling protein (MAVS) and interferon regulatory factor 3 (IRF3). Depletion of MAVS or IRF3, or overexpression of the MAVS-inactivating HCV NS3/4A protease not only blocked interferon responses but also restored cell growth in NS5B expressing cells. However, pan-caspase inhibition could not rescue the NS5B-induced cytostasis. Our results underline an active counter selection of cells with prolonged innate immune activation, which likely constitutes a cellular strategy to prevent persistent virus infections. 
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