Identification of Interleukin1β as an Amplifier of Interferon alpha-induced Antiviral Responses

Katharina Robichon; Tim Maiwald; Marcel Schilling; Annette Schneider; Joschka Willemsen; Florian Salopiata; Melissa Teusel; Clemens Kreutz; Christian Ehlting; Jun Huang; Sajib Chakraborty; Xiaoyun Huang; Georg Damm; Daniel Seehofer; Philipp A Lang; Johannes G Bode; Marco Binder; Ralf Bartenschlager; Jens Timmer; Ursula Klingmüller

doi:10.1371/journal.ppat.1008461

Identification of Interleukin1β as an Amplifier of Interferon alpha-induced Antiviral Responses

PLoS Pathog. 2020 Oct 1;16(10):e1008461. doi: 10.1371/journal.ppat.1008461. eCollection 2020 Oct.

Authors

Katharina Robichon¹, Tim Maiwald^{2

3}, Marcel Schilling¹, Annette Schneider¹, Joschka Willemsen⁴, Florian Salopiata¹, Melissa Teusel¹, Clemens Kreutz^{2

5}, Christian Ehlting⁶, Jun Huang⁷, Sajib Chakraborty^{1

8}, Xiaoyun Huang¹, Georg Damm⁹, Daniel Seehofer⁹, Philipp A Lang⁷, Johannes G Bode⁶, Marco Binder⁴, Ralf Bartenschlager¹⁰, Jens Timmer^{2

3

11}, Ursula Klingmüller¹

Affiliations

¹ Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany.
² Institute for Physics, University of Freiburg, Germany.
³ FDM-Freiburg Center for Data Analysis and Modeling, University of Freiburg, Freiburg, Germany.
⁴ Research Group "Dynamics of Early Viral Infection and the Innate Antiviral Response", Division Virus-Associated Carcinogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵ Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
⁶ Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Germany.
⁷ Department of Molecular Medicine II, University Hospital, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Germany.
⁸ Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh.
⁹ Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, Leipzig, Germany and Department of General-, Visceral- and Transplantation Surgery, Charité University Medicine Berlin, Berlin, Germany.
¹⁰ Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany.
¹¹ Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.

Abstract

The induction of an interferon-mediated response is the first line of defense against pathogens such as viruses. Yet, the dynamics and extent of interferon alpha (IFNα)-induced antiviral genes vary remarkably and comprise three expression clusters: early, intermediate and late. By mathematical modeling based on time-resolved quantitative data, we identified mRNA stability as well as a negative regulatory loop as key mechanisms endogenously controlling the expression dynamics of IFNα-induced antiviral genes in hepatocytes. Guided by the mathematical model, we uncovered that this regulatory loop is mediated by the transcription factor IRF2 and showed that knock-down of IRF2 results in enhanced expression of early, intermediate and late IFNα-induced antiviral genes. Co-stimulation experiments with different pro-inflammatory cytokines revealed that this amplified expression dynamics of the early, intermediate and late IFNα-induced antiviral genes can also be achieved by co-application of IFNα and interleukin1 beta (IL1β). Consistently, we found that IL1β enhances IFNα-mediated repression of viral replication. Conversely, we observed that in IL1β receptor knock-out mice replication of viruses sensitive to IFNα is increased. Thus, IL1β is capable to potentiate IFNα-induced antiviral responses and could be exploited to improve antiviral therapies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents / pharmacology
Gene Expression Regulation, Viral / drug effects*
Hepatocytes / cytology
Hepatocytes / drug effects
Hepatocytes / immunology
Hepatocytes / virology
Humans
Interferon Regulatory Factor-2 / genetics
Interferon Regulatory Factor-2 / metabolism*
Interferon-alpha / pharmacology*
Lymphocytic Choriomeningitis / drug therapy*
Lymphocytic Choriomeningitis / immunology
Lymphocytic Choriomeningitis / pathology
Lymphocytic Choriomeningitis / virology
Lymphocytic choriomeningitis virus / drug effects*
Lymphocytic choriomeningitis virus / isolation & purification
Mice
Mice, Inbred C57BL
Mice, Knockout
RNA Stability
Receptors, Interleukin-1 Type I / physiology*
Virus Replication / drug effects*

Substances

Antiviral Agents
IL1R1 protein, mouse
Interferon Regulatory Factor-2
Interferon-alpha
Receptors, Interleukin-1 Type I

Grants and funding

Funding: This study was funded by the German Ministry for Education (BMBF) (https://www.bmbf.de/) within the grants FORSYS initiative ViroQuant (0313923 to AS, TM, RB, UK), the e:Bio network ImmunoQuant (0316170B to KR, UK; 0316170C to JW, MBi, RB), the Virtual Liver Network (0315745 to XH, UK; 0315766 to JT, CK; 0315713 to JGB; 0315741 to GD, DS), the EraSysAPP consortium IMOMESIC (031A604A to UK; 031A604B JT; 031A604C to GD, DS) and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (https://www.dfg.de/) – Projektnummer 272983813 – TRR 179 (to RB, UK, MT, JT, MBi), Projektnummer 190586431 - SFB 974 (to PAL, JGB) and Projektnummer 231604701 - GRK 1949 (to PAL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.