Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Interferon modulation of cellular microRNAs as an antiviral mechanism

Nature volume 449, pages 919–922 (2007)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Cullen, B. R. Is RNA interference involved in intrinsic antiviral immunity in mammals? Nature Immunol. 7, 563–567 (2006)

    Article  CAS  Google Scholar 

  2. Jopling, C. L., Yi, M., Lancaster, A. M., Lemon, S. M. & Sarnow, P. Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA. Science 309, 1577–1581 (2005)

    Article  ADS  CAS  Google Scholar 

  3. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004)

    Article  CAS  Google Scholar 

  4. Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004)

    Article  ADS  CAS  Google Scholar 

  5. Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005)

    Article  CAS  Google Scholar 

  6. Zamore, P. D. Plant RNAi: How a viral silencing suppressor inactivates siRNA. Curr. Biol. 14, R198–R200 (2004)

    Article  CAS  Google Scholar 

  7. Baulcombe, D. RNA silencing in plants. Nature 431, 356–363 (2004)

    Article  ADS  CAS  Google Scholar 

  8. Katze, M. G., He, Y. & Gale, M. Viruses and interferon: a fight for supremacy. Nature Rev. Immunol. 2, 675–687 (2002)

    Article  CAS  Google Scholar 

  9. Samuel, C. E. Antiviral actions of interferons. Clin. Microbiol. Rev. 14, 778–809 (2001)

    Article  CAS  Google Scholar 

  10. Liang, T. J., Rehermann, B., Seeff, L. B. & Hoofnagle, J. H. Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann. Intern. Med. 132, 296–305 (2000)

    Article  CAS  Google Scholar 

  11. Lauer, G. M. & Walker, B. D. Hepatitis C virus infection. N. Engl. J. Med. 345, 41–52 (2001)

    Article  CAS  Google Scholar 

  12. Wieland, S. F. & Chisari, F. V. Stealth and cunning: hepatitis B and hepatitis C viruses. J. Virol. 79, 9369–9380 (2005)

    Article  CAS  Google Scholar 

  13. Rehermann, B. & Nascimbeni, M. Immunology of hepatitis B virus and hepatitis C virus infection. Nature Rev. Immunol. 5, 215–229 (2005)

    Article  CAS  Google Scholar 

  14. Larner, A. C. et al. Transcriptional induction of two genes in human cells by beta interferon. Proc. Natl Acad. Sci. USA 81, 6733–6737 (1984)

    Article  ADS  CAS  Google Scholar 

  15. Randall, G. et al. Cellular cofactors affecting hepatitis C virus infection and replication. Proc. Natl Acad. Sci. USA 104, 12884–12889 (2007)

    Article  ADS  CAS  Google Scholar 

  16. Zhong, J. et al. Robust hepatitis C virus infection in vitro . Proc. Natl Acad. Sci. USA 102, 9294–9299 (2005)

    Article  ADS  CAS  Google Scholar 

  17. Moradpour, D. et al. Insertion of green fluorescent protein into nonstructural protein 5A allows direct visualization of functional hepatitis C virus replication complexes. J. Virol. 78, 7400–7409 (2004)

    Article  CAS  Google Scholar 

  18. Calin, G. A. & Croce, C. M. MicroRNA–cancer connection: the beginning of a new tale. Cancer Res. 66, 7390–7394 (2006)

    Article  CAS  Google Scholar 

  19. Calin, G. A. & Croce, C. M. MicroRNA signatures in human cancers. Nature Rev. Cancer 6, 857–866 (2006)

    Article  ADS  CAS  Google Scholar 

  20. O'Connell, R. M., Taganov, K. D., Boldin, M. P., Cheng, G. & Baltimore, D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc. Natl Acad. Sci. USA 104, 1604–1609 (2007)

    Article  ADS  CAS  Google Scholar 

  21. Kato, T. et al. Efficient replication of the genotype 2a hepatitis C virus subgenomic replicon. Gastroenterology 125, 1808–1817 (2003)

    Article  CAS  Google Scholar 

  22. Cheng, G., Zhong, J. & Chisari, F. V. Inhibition of dsRNA-induced signaling in hepatitis C virus-infected cells by NS3 protease-dependent and -independent mechanisms. Proc. Natl Acad. Sci. USA 103, 8499–8504 (2006)

    Article  ADS  CAS  Google Scholar 

  23. Liu, C. G. et al. An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues. Proc. Natl Acad. Sci. USA 101, 9740–9744 (2004)

    Article  ADS  CAS  Google Scholar 

  24. Yanagi, M., Purcell, R. H., Emerson, S. U. & Bukh, J. Hepatitis C virus: an infectious molecular clone of a second major genotype (2a) and lack of viability of intertypic 1a and 2a chimeras. Virology 262, 250–263 (1999)

    Article  CAS  Google Scholar 

  25. Wakita, T. et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nature Med. 11, 791–796 (2005)

    Article  CAS  Google Scholar 

  26. Pietschmann, T. et al. Construction and characterization of infectious intragenotypic and intergenotypic hepatitis C virus chimeras. Proc. Natl Acad. Sci. USA 103, 7408–7413 (2006)

    Article  ADS  CAS  Google Scholar 

  27. Zhong, J. et al. Robust hepatitis C virus infection in vitro . Proc. Natl Acad. Sci. USA 102, 9294–9299 (2005)

    Article  ADS  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  1. Division of Biological Sciences, and,

Authors and Affiliations

  1. Department of Molecular Biology,,

    Irene M. Pedersen & Michael David

  2. Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA ,

    Michael David

  3. Division of Experimental Pathology, The Scripps Research Institute, La Jolla, California 92037, USA,

    Guofeng Cheng, Stefan Wieland & Francis V. Chisari

  4. Department of Molecular Virology, Immunology & Medical Genetics, Ohio State University, Columbus, Ohio 43210, USA,

    Stefano Volinia & Carlo M. Croce

Authors
  1. Irene M. Pedersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guofeng Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stefan Wieland
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stefano Volinia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carlo M. Croce
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Francis V. Chisari
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael David
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael David.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

The file contains Supplementary Figures 1 and 2 with Legends. (PDF 5004 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06205

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing