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Open AccessArticle

Persistent Innate Immune Stimulation Results in IRF3-Mediated but Caspase-Independent Cytostasis

1
Institute of Virology, School of Medicine, Technical University of Munich, 81675 Munich, Germany
2
Research Group “Dynamics of Early Viral Infection and the Innate Antiviral Response”, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
3
Faculty of Biosciences, Heidelberg University, 69117 Heidelberg, Germany
4
German Center for Infection Research (DZIF), Munich Partner Site, 81675 Munich, Germany
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Viruses 2020, 12(6), 635; https://doi.org/10.3390/v12060635
Received: 2 May 2020 / Revised: 9 June 2020 / Accepted: 9 June 2020 / Published: 11 June 2020
(This article belongs to the Special Issue Innate Immune Sensing of Viruses and Viral Evasion)
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. View Full-Text
Keywords: innate immunity; RIG-I; MAVS; IRF3; interferon; HCV; cytostasis innate immunity; RIG-I; MAVS; IRF3; interferon; HCV; cytostasis
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Urban, C.; Welsch, H.; Heine, K.; Wüst, S.; Haas, D.A.; Dächert, C.; Pandey, A.; Pichlmair, A.; Binder, M. Persistent Innate Immune Stimulation Results in IRF3-Mediated but Caspase-Independent Cytostasis. Viruses 2020, 12, 635.

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