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

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 and Golo Ahlenstiel ()
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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
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

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15245

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