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

Klingmüller, U.; Robichon, K.; Maiwald, T.; Schilling, M.; Schneider, A.; Willemsen, J.; Salopiata, F.; Teusel, M.; Kreutz, C.; Ehlting, C.; Huang, J.; Chakraborty, S.; Huang, X.; Damm, G.; Seehofer, D.; Lang, P. A.; Bode, J. G.; Binder, M.; Bartenschlager, R.; Timmer, J.

doi:10.1101/2020.03.10.985390

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bioRxiv · 10.1101/2020.03.10.985390

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

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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 (IFN)-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 IFN-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 IFN-induced antiviral genes. Co-stimulation experiments with different pro-inflammatory cytokines revealed that this amplified expression dynamics of the early, intermediate and late IFN-induced antiviral genes can be mimicked by co-application of IFN and interleukin1 beta (IL1{beta}). Consistently, we found that IL1{beta} enhances IFN-mediated repression of viral replication. Conversely, we observed that in IL1{beta} receptor knock-out mice replication of viruses sensitive to IFN is increased. Thus, IL1{beta} is capable to potentiate IFN-induced antiviral responses and could be exploited to improve antiviral therapies. Author SummaryInnate immune responses contribute to the control of viral infections and the induction of interferon alpha (IFN)-mediated antiviral responses is an important component. However, IFN induces a multitude of antiviral response genes and the expression dynamics of these genes can be classified as early, intermediate and late. Here we show, based on a mathematical modeling approach, that mRNA stability as well as the negative regulator IRF2 control the expression dynamics of IFN-induced antiviral genes. Knock-down of IRF2 resulted in the amplified IFN-mediated induction of the antiviral genes and this amplified expression of antiviral genes could be mimicked by co-stimulation with IFN and IL1{beta}. We observed that co-stimulation with IFN and IL1{beta} enhanced the repression of virus replication and that knock-out of the IL1 receptor in mice resulted in increased replication of a virus sensitive to IFN. In sum, our studies identified IL1{beta} as an important amplifier of IFN-induced antiviral responses.

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Klingmüller, U., Robichon, K., Maiwald, T., Schilling, M., Schneider, A., Willemsen, J., Salopiata, F., Teusel, M., Kreutz, C., Ehlting, C., Huang, J., Chakraborty, S., Huang, X., Damm, G., Seehofer, D., Lang, P. A., Bode, J. G., Binder, M., Bartenschlager, R., Timmer, J.. 2020-03-10. Identification of Interleukin1β as an Amplifier of Interferon alpha-induced Antiviral Responses. https://doi.org/10.1101/2020.03.10.985390

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