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; Golo Ahlenstiel

doi:10.1038/ncomms15245

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, Golo Ahlenstiel

Research output: Contribution to journal › Article › peer-review

45 Citations (Scopus)

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.

Original language	English
Article number	15245
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15245
Publication status	Published or Issued - 17 May 2017
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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title = "Zinc is a potent and specific inhibitor of IFN-λ3 signalling",

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.",

author = "Read, {Scott A.} and O'Connor, {Kate S.} and Vijay Suppiah and Ahlenstiel, {Chantelle L.E.} and Stephanie Obeid and Cook, {Kristina M.} and Anthony Cunningham and Douglas, {Mark W.} and Hogg, {Philip J.} and David Booth and Jacob George and Golo Ahlenstiel",

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doi = "10.1038/ncomms15245",

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AU - Read, Scott A.

AU - O'Connor, Kate S.

AU - Suppiah, Vijay

AU - Ahlenstiel, Chantelle L.E.

AU - Obeid, Stephanie

AU - Cook, Kristina M.

AU - Cunningham, Anthony

AU - Douglas, Mark W.

AU - Hogg, Philip J.

AU - Booth, David

AU - George, Jacob

AU - Ahlenstiel, Golo

PY - 2017/5/17

Y1 - 2017/5/17

N2 - 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.

AB - 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.

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VL - 8

JO - Nature communications

JF - Nature communications

SN - 2041-1723

M1 - 15245

ER -

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

Abstract

ASJC Scopus subject areas

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