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Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA

Nature volume 454, pages 523–527 (2008)Cite this article

Abstract

Innate immune defences are essential for the control of virus infection and are triggered through host recognition of viral macromolecular motifs known as pathogen-associated molecular patterns (PAMPs)1. Hepatitis C virus (HCV) is an RNA virus that replicates in the liver, and infects 200 million people worldwide2. Infection is regulated by hepatic immune defences triggered by the cellular RIG-I helicase. RIG-I binds PAMP RNA and signals interferon regulatory factor 3 activation to induce the expression of interferon-α/β and antiviral/interferon-stimulated genes (ISGs) that limit infection3,4,5,6,7,8,9,10. Here we identify the polyuridine motif of the HCV genome 3′ non-translated region and its replication intermediate as the PAMP substrate of RIG-I, and show that this and similar homopolyuridine or homopolyriboadenine motifs present in the genomes of RNA viruses are the chief feature of RIG-I recognition and immune triggering in human and murine cells8. 5′ terminal triphosphate on the PAMP RNA was necessary but not sufficient for RIG-I binding, which was primarily dependent on homopolymeric ribonucleotide composition, linear structure and length. The HCV PAMP RNA stimulated RIG-I-dependent signalling to induce a hepatic innate immune response in vivo, and triggered interferon and ISG expression to suppress HCV infection in vitro. These results provide a conceptual advance by defining specific homopolymeric RNA motifs within the genome of HCV and other RNA viruses as the PAMP substrate of RIG-I, and demonstrate immunogenic features of the PAMP–RIG-I interaction that could be used as an immune adjuvant for vaccine and immunotherapy approaches.

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Figure 1: Identification of HCV PAMP RNA.
Figure 2: RIG-I-specific HCV RNA PAMP recognition and signalling.
Figure 3: Polyuridine and polyriboadenine ribonucleotides are RIG-I ligands.
Figure 4: HCV PAMP RNA triggers the hepatic innate immune response and anti-HCV defences.

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Acknowledgements

We thank T. Fujita for discussions, and S. Horner for manuscript review. We thank T. Fujita, S. Lemon, G. Sen, C. Rice, T. Taniguchi, A. Miyawaki, S. Akira for reagents, R. Hirai for technical consultation, and J. Briley, S. Thomas and G. Martin for technical assistance. This work was supported by funds from the State of Washington, National Institutes of Health grants R01AI060389, R01DA021353, U19AI40035 (Project 4) and the Burroughs-Wellcome Fund, and by a gift from Mr. and Mrs. R. Batcheldor.

Author Contributions T.S. conducted RNA binding studies and RIG-I signalling analyses. T.S. and D.M.O. conducted in vivo studies. F.J. and J.M. developed the RIG-I protein-expression system, and produced, purified and tested recombinant RIG-I proteins. M.G. directed the research. All authors participated in study design and manuscript preparation. T.S. wrote the manuscript.

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Authors and Affiliations

  1. Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98195-7650, USA,

    Takeshi Saito, David M. Owen & Michael Gale Jr.

  2. Department of Microbiology, UT Southwestern Medical Center, Dallas, Texas 75235-9048, USA,

    David M. Owen

  3. Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854, USA,

    Fuguo Jiang & Joseph Marcotrigiano

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  1. Takeshi Saito
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Correspondence to Michael Gale Jr..

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Supplementary Information

The file contains Supplementary Methods, Supplementary Tables S1-S2 and Supplementary Figures S1-S7 with legends and additional references. (PDF 1189 kb)

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Saito, T., Owen, D., Jiang, F. et al. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454, 523–527 (2008). https://doi.org/10.1038/nature07106

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