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MicroRNAs regulate the immunometabolic response to viral infection in the liver

Nature Chemical Biology volume 11, pages 988–993 (2015)Cite this article

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Abstract

Immune regulation of cellular metabolism can be responsible for successful responses to invading pathogens. Viruses alter their hosts' cellular metabolism to facilitate infection. Conversely, the innate antiviral responses of mammalian cells target these metabolic pathways to restrict viral propagation. We identified miR-130b and miR-185 as hepatic microRNAs (miRNAs) whose expression is stimulated by 25-hydroxycholesterol (25-HC), an antiviral oxysterol secreted by interferon-stimulated macrophages and dendritic cells, during hepatitis C virus (HCV) infection. However, 25-HC only directly stimulated miR-185 expression, whereas HCV regulated miR-130b expression. Independently, miR-130b and miR-185 inhibited HCV infection. In particular, miR-185 significantly restricted host metabolic pathways crucial to the HCV life cycle. Interestingly, HCV infection decreased miR-185 and miR-130b levels to promote lipid accumulation and counteract 25-HC's antiviral effect. Furthermore, miR-185 can inhibit other viruses through the regulation of immunometabolic pathways. These data establish these microRNAs as a key link between innate defenses and metabolism in the liver.

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Figure 1: 25-HC and HCV oppositely regulate miRNA expression.
Figure 2: 25-HC–stimulated miRNAs inhibit HCV life cycle.
Figure 3: 25-HC stimulated miRNAs regulate hepatic lipid metabolism.
Figure 4: HCV infection in vivo disrupts hepatic lipid metabolism.
Figure 5: miR-185 inhibits HCV replication through regulation of lipid microenvironments.

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Acknowledgements

We thank A. Ridsdale and the National Research Council of Canada (NRC) coherent anti-Stokes Raman spectroscopy (CARS) facility along with Z. Jakubek and the NRC measurement science and standards (MSS) imaging facility for technical assistance. mRNA microarray profiling was performed by the Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada. Lipid profiling was performed by A. Moses and the Lipid Analysis Core Service, University of Alberta, Edmonton, Alberta, Canada. We also would like to thank E. Riklow for assistance with Dengue virus experiments. This study was supported by funding from Natural Sciences and Engineering Research Council (NSERC) of Canada grant (298496 to J.P.P.) and Canadian Institutes of Health Research (CIHR) grants (136807, 232063 to J.P.P., R.S.R. and D.L.T.; 130365 to K.J.R.; 28637 to T.C.H.). R.S., D.M.J., R.C. and N.G.T. would like to thank the National CIHR Research Training Program in Hepatitis C (NCRTP-HepC) for training and funding. R.S. was supported by a Vanier Canadian Graduate scholarship. D.G.R. was supported by a CIHR graduate scholarship. D.Ö. was supported by a post-doctoral fellowship from the CIHR. A.K. was supported by NSERC–Collaborative Research and Training Experience (CREATE) and Alberta Innovates–Health Solutions postdoctoral fellowships. T.C.H. was supported by a Tier 1 Canada Research Chair.

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Authors and Affiliations

  1. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada

    Ragunath Singaravelu, Prashanth Srinivasan, Curtis Quan, My-Anh Nguyen, Katey J Rayner & John Paul Pezacki

  2. Life Sciences Division, National Research Council of Canada, Ottawa, Ontario, Canada

    Ragunath Singaravelu, Shifawn O'Hara, Prashanth Srinivasan, Curtis Quan, Rodney K Lyn, Dennis Özcelik, Yanouchka Rouleau & John Paul Pezacki

  3. Immunology and Infectious Diseases, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada

    Daniel M Jones, Nathan G Taylor & Rodney S Russell

  4. Department of Medical Microbiology and Immunology, University of Alberta and Li Ka Shing Institute of Virology, Katz Centre for Pharmacy and Health Research, Edmonton, Alberta, Canada

    Ran Chen, Rineke H Steenbergen & David Lorne Tyrrell

  5. Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

    Dominic G Roy

  6. Department of Cell Biology, University of Alberta, Edmonton, Alberta, Canada

    Anil Kumar & Tom C Hobman

  7. Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, Canada

    Rodney K Lyn, Dennis Özcelik & John Paul Pezacki

  8. University of Ottawa Heart Institute, Ottawa, Ontario, Canada

    My-Anh Nguyen & Katey J Rayner

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  1. Ragunath Singaravelu
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Contributions

R.S., K.J.R., T.C.H., D.L.T., R.S.R. and J.P.P. conceived and designed experiments. R.S., S.O'H., D.M.J., N.G.T. and R.S.R. performed cell culture and sample collection for experiments using JFH-1T. R.S. and R.H.S. performed cell culture and sample collection for experiments using JFH-HS. R.S. and R.K.L. performed CARS microscopy experiments. R.C. and D.L.T. performed mice experiments. M.-A.N and K.J.R. performed macrophage cell culture and sample collection. R.C. performed lipid analysis and immunofluorescence. R.S. and A.K. performed cell culture and sample collection for experiments dealing with DENV. R.S. and D.G.R. performed cell culture and sample collection for experiments dealing with VSV. R.S., S.O'H., P.S., C.Q., D.Ö. and Y.R. performed all sample processing and downstream analysis. R.S., R.S.R. and J.P.P. analyzed the data. R.S. and J.P.P. wrote the manuscript.

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Correspondence to John Paul Pezacki.

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Singaravelu, R., O'Hara, S., Jones, D. et al. MicroRNAs regulate the immunometabolic response to viral infection in the liver. Nat Chem Biol 11, 988–993 (2015). https://doi.org/10.1038/nchembio.1940

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