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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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Hauptverfasser: Urban, Christian (VerfasserIn) , Welsch, Hendrik (VerfasserIn) , Heine, Katharina (VerfasserIn) , Wüst, Sandra (VerfasserIn) , Haas, Darya A. (VerfasserIn) , Dächert, Christopher (VerfasserIn) , Pandey, Aparna (VerfasserIn) , Pichlmair, Andreas (VerfasserIn) , Binder, Marco (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 11 June 2020
In: Viruses
Year: 2020, Jahrgang: 12, Heft: 6
ISSN:1999-4915
DOI:10.3390/v12060635
Online-Zugang: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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Verfasserangaben:Christian Urban, Hendrik Welsch, Katharina Heine, Sandra Wüst, Darya A. Haas, Christopher Dächert, Aparna Pandey, Andreas Pichlmair and Marco Binder
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Zusammenfassung: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.
Beschreibung:Gesehen am 02.09.2020
Beschreibung:Online Resource
ISSN:1999-4915
DOI:10.3390/v12060635

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