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Open AccessArticle

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

Institute of Virology, School of Medicine, Technical University of Munich, 81675 Munich, Germany
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
Faculty of Biosciences, Heidelberg University, 69117 Heidelberg, Germany
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;
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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