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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-06-01
|
| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/12/6/635 |
| _version_ | 1797565550836056064 |
|---|---|
| author | Christian Urban Hendrik Welsch Katharina Heine Sandra Wüst Darya A. Haas Christopher Dächert Aparna Pandey Andreas Pichlmair Marco Binder |
| author_facet | Christian Urban Hendrik Welsch Katharina Heine Sandra Wüst Darya A. Haas Christopher Dächert Aparna Pandey Andreas Pichlmair Marco Binder |
| author_sort | Christian Urban |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T19:13:51Z |
| format | Article |
| id | doaj.art-394f1316bf0f4c35a8f831e009c5e958 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-10T19:13:51Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-394f1316bf0f4c35a8f831e009c5e9582023-11-20T03:32:17ZengMDPI AGViruses1999-49152020-06-0112663510.3390/v12060635Persistent Innate Immune Stimulation Results in IRF3-Mediated but Caspase-Independent CytostasisChristian Urban0Hendrik Welsch1Katharina Heine2Sandra Wüst3Darya A. Haas4Christopher Dächert5Aparna Pandey6Andreas Pichlmair7Marco Binder8Institute of Virology, School of Medicine, Technical University of Munich, 81675 Munich, GermanyResearch Group “Dynamics of Early Viral Infection and the Innate Antiviral Response”, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, GermanyResearch Group “Dynamics of Early Viral Infection and the Innate Antiviral Response”, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, GermanyResearch Group “Dynamics of Early Viral Infection and the Innate Antiviral Response”, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, GermanyInstitute of Virology, School of Medicine, Technical University of Munich, 81675 Munich, GermanyResearch Group “Dynamics of Early Viral Infection and the Innate Antiviral Response”, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, GermanyResearch Group “Dynamics of Early Viral Infection and the Innate Antiviral Response”, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, GermanyInstitute of Virology, School of Medicine, Technical University of Munich, 81675 Munich, GermanyResearch Group “Dynamics of Early Viral Infection and the Innate Antiviral Response”, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, GermanyPersistent 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.https://www.mdpi.com/1999-4915/12/6/635innate immunityRIG-IMAVSIRF3interferonHCV |
| spellingShingle | Christian Urban Hendrik Welsch Katharina Heine Sandra Wüst Darya A. Haas Christopher Dächert Aparna Pandey Andreas Pichlmair Marco Binder Persistent Innate Immune Stimulation Results in IRF3-Mediated but Caspase-Independent Cytostasis Viruses innate immunity RIG-I MAVS IRF3 interferon HCV |
| title | Persistent Innate Immune Stimulation Results in IRF3-Mediated but Caspase-Independent Cytostasis |
| title_full | Persistent Innate Immune Stimulation Results in IRF3-Mediated but Caspase-Independent Cytostasis |
| title_fullStr | Persistent Innate Immune Stimulation Results in IRF3-Mediated but Caspase-Independent Cytostasis |
| title_full_unstemmed | Persistent Innate Immune Stimulation Results in IRF3-Mediated but Caspase-Independent Cytostasis |
| title_short | Persistent Innate Immune Stimulation Results in IRF3-Mediated but Caspase-Independent Cytostasis |
| title_sort | persistent innate immune stimulation results in irf3 mediated but caspase independent cytostasis |
| topic | innate immunity RIG-I MAVS IRF3 interferon HCV |
| url | https://www.mdpi.com/1999-4915/12/6/635 |
| work_keys_str_mv | AT christianurban persistentinnateimmunestimulationresultsinirf3mediatedbutcaspaseindependentcytostasis AT hendrikwelsch persistentinnateimmunestimulationresultsinirf3mediatedbutcaspaseindependentcytostasis AT katharinaheine persistentinnateimmunestimulationresultsinirf3mediatedbutcaspaseindependentcytostasis AT sandrawust persistentinnateimmunestimulationresultsinirf3mediatedbutcaspaseindependentcytostasis AT daryaahaas persistentinnateimmunestimulationresultsinirf3mediatedbutcaspaseindependentcytostasis AT christopherdachert persistentinnateimmunestimulationresultsinirf3mediatedbutcaspaseindependentcytostasis AT aparnapandey persistentinnateimmunestimulationresultsinirf3mediatedbutcaspaseindependentcytostasis AT andreaspichlmair persistentinnateimmunestimulationresultsinirf3mediatedbutcaspaseindependentcytostasis AT marcobinder persistentinnateimmunestimulationresultsinirf3mediatedbutcaspaseindependentcytostasis |