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Zinc is a potent and specific inhibitor of IFN-λ3 signalling

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  • Scott A. Read

    (Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital)

  • Kate S. O’Connor

    (Centre for Immunology and Allergy Research, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital)

  • Vijay Suppiah

    (School of Pharmacy and Medical Science, University of South Australia)

  • Chantelle L. E. Ahlenstiel

    (The Kirby Institute for Infection and Immunity in Society, University of New South Wales)

  • Stephanie Obeid

    (Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital)

  • Kristina M. Cook

    (The Centenary Institute)

  • Anthony Cunningham

    (Centre of Virus Research, Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital)

  • Mark W. Douglas

    (Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital
    Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital)

  • Philip J. Hogg

    (National Health and Medical Research Council Clinical Trials Centre, University of Sydney)

  • David Booth

    (Centre for Immunology and Allergy Research, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital)

  • Jacob George

    (Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital)

  • Golo Ahlenstiel

    (Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital)

Abstract

Lambda interferons (IFNL, IFN-λ) are pro-inflammatory cytokines important in acute and chronic viral infection. Single-nucleotide polymorphisms rs12979860 and rs8099917 within the IFNL gene locus predict hepatitis C virus (HCV) clearance, as well as inflammation and fibrosis progression in viral and non-viral liver disease. The underlying mechanism, however, is not defined. Here we show that the rs12979860 CC genotype correlates with increased hepatic metallothionein expression through increased systemic zinc levels. Zinc interferes with IFN-λ3 binding to IFNL receptor 1 (IFNLR1), resulting in decreased antiviral activity and increased viral replication (HCV, influenza) in vitro. HCV patients with high zinc levels have low hepatocyte antiviral and inflammatory gene expression and high viral loads, confirming the inhibitory role of zinc in vivo. We provide the first evidence that zinc can act as a potent and specific inhibitor of IFN-λ3 signalling and highlight its potential as a target of therapeutic intervention for IFN-λ3-mediated chronic disease.

Suggested Citation

  • Scott A. Read & Kate S. O’Connor & Vijay Suppiah & Chantelle L. E. Ahlenstiel & Stephanie Obeid & Kristina M. Cook & Anthony Cunningham & Mark W. Douglas & Philip J. Hogg & David Booth & Jacob George , 2017. "Zinc is a potent and specific inhibitor of IFN-λ3 signalling," Nature Communications, Nature, vol. 8(1), pages 1-15, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15245
    DOI: 10.1038/ncomms15245
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