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

Western Sydney University

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

50 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
Number of pages	15
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15245
Publication status	Published - 2017

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This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Keywords

hepatitis C virus
zinc

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms15245

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@article{acd29004115448d3a97a173b38427941,

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.",

keywords = "hepatitis C virus, zinc",

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",

year = "2017",

doi = "10.1038/ncomms15245",

language = "English",

volume = "8",

journal = "Nature Communications",

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TY - JOUR

T1 - Zinc is a potent and speciﬁc inhibitor of IFN-λ3 signalling

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

Y1 - 2017

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.

KW - hepatitis C virus

KW - zinc

UR - http://handle.westernsydney.edu.au:8081/1959.7/uws:41487

U2 - 10.1038/ncomms15245

DO - 10.1038/ncomms15245

M3 - Article

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 15245

ER -

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

Abstract

Open Access - Access Right Statement

Keywords

UN SDGs

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