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Interferon modulation of cellular microRNAs as an antiviral mechanism

Abstract

RNA interference through non-coding microRNAs (miRNAs) represents a vital component of the innate antiviral immune response in plants and invertebrate animals; however, a role for cellular miRNAs in the defence against viral infection in mammalian organisms has thus far remained elusive1. Here we show that interferon beta (IFNβ) rapidly modulates the expression of numerous cellular miRNAs, and that eight of these IFNβ-induced miRNAs have sequence-predicted targets within the hepatitis C virus (HCV) genomic RNA. The introduction of synthetic miRNA-mimics corresponding to these IFNβ-induced miRNAs reproduces the antiviral effects of IFNβ on HCV replication and infection, whereas neutralization of these antiviral miRNAs with anti-miRNAs reduces the antiviral effects of IFNβ against HCV. In addition, we demonstrate that IFNβ treatment leads to a significant reduction in the expression of the liver-specific miR-122, an miRNA that has been previously shown to be essential for HCV replication2. Therefore, our findings strongly support the notion that mammalian organisms too, through the interferon system, use cellular miRNAs to combat viral infections.

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Figure 1: Regulation of miRNA expression by IFNβ in Huh7 cells and primary hepatocytes.
Figure 2: IFNβ-induced miRNAs display anti-viral activity against HCV.
Figure 3: IFNβ-induced miRNAs directly target viral genomic RNA.
Figure 4: IFNβ-induced miRNAs mediate anti-viral IFNβ responses against HCV.

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Acknowledgements

We thank G. Calin (OSU) for help with the microarray studies, D. Burton (TSRI) for E2-antibodies, and J. Zhong (TSRI) for many discussions. This work was supported by the NIH (I.M.P.), a private donation from C. Evans to F.V.C, and the NIH and UCSD Academic Senate Funding (M.D.).

Author Contributions G.C. and S.W. contributed equally to this work.

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Correspondence to Michael David.

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Pedersen, I., Cheng, G., Wieland, S. et al. Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 449, 919–922 (2007). https://doi.org/10.1038/nature06205

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