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Open Access

Direct Antiviral Activity of IFN-Stimulated Genes Is Responsible for Resistance to Paramyxoviruses in ISG15-Deficient Cells

David Holthaus, Andri Vasou, Connor G. G. Bamford, Jelena Andrejeva, Christina Paulus, Richard E. Randall, John McLauchlan and David J. Hughes
J Immunol May 18, 2020, ji1901472; DOI: https://doi.org/10.4049/jimmunol.1901472
David Holthaus
*Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St Andrews KY16 9ST, United Kingdom; and
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Andri Vasou
*Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St Andrews KY16 9ST, United Kingdom; and
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Connor G. G. Bamford
†MRC-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, United Kingdom
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Jelena Andrejeva
*Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St Andrews KY16 9ST, United Kingdom; and
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Christina Paulus
*Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St Andrews KY16 9ST, United Kingdom; and
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Richard E. Randall
*Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St Andrews KY16 9ST, United Kingdom; and
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John McLauchlan
†MRC-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, United Kingdom
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David J. Hughes
*Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St Andrews KY16 9ST, United Kingdom; and
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Key Points

  • Cell culture model of ISG15 deficiency replicates findings in ISG15−/− patient cells.

  • Cause of resistance in ISG15−/− cells differs depending on duration of IFN treatment.

  • ISG15−/− patients without serious viral disease do not prove ISGylation is unimportant.

Abstract

IFNs, produced during viral infections, induce the expression of hundreds of IFN-stimulated genes (ISGs). Some ISGs have specific antiviral activity, whereas others regulate the cellular response. Besides functioning as an antiviral effector, ISG15 is a negative regulator of IFN signaling, and inherited ISG15 deficiency leads to autoinflammatory IFNopathies, in which individuals exhibit elevated ISG expression in the absence of pathogenic infection. We have recapitulated these effects in cultured human A549-ISG15−/− cells and (using A549-UBA7−/− cells) confirmed that posttranslational modification by ISG15 (ISGylation) is not required for regulation of the type I IFN response. ISG15-deficient cells pretreated with IFN-α were resistant to paramyxovirus infection. We also showed that IFN-α treatment of ISG15-deficient cells led to significant inhibition of global protein synthesis, leading us to ask whether resistance was due to the direct antiviral activity of ISGs or whether cells were nonpermissive because of translation defects. We took advantage of the knowledge that IFN-induced protein with tetratricopeptide repeats 1 (IFIT1) is the principal antiviral ISG for parainfluenza virus 5. Knockdown of IFIT1 restored parainfluenza virus 5 infection in IFN-α–pretreated, ISG15-deficient cells, confirming that resistance was due to the direct antiviral activity of the IFN response. However, resistance could be induced if cells were pretreated with IFN-α for longer times, presumably because of inhibition of protein synthesis. These data show that the cause of virus resistance is 2-fold; ISG15 deficiency leads to the early overexpression of specific antiviral ISGs, but the later response is dominated by an unanticipated, ISG15-dependent loss of translational control.

Footnotes

  • This work was supported by Academy of Medical Sciences Grant SBF003/1028, Wellcome Trust Grant 101788/Z/13/Z, U.K. Research and Innovation, Medical Research Council Grant MC_UU_12014/1, and Erasmus+ (to D.H.).

  • The online version of this article contains supplemental material.

  • Received December 12, 2019.
  • Accepted April 23, 2020.
  • Copyright © 2020 The Authors

This article is distributed under the terms of the CC BY 4.0 Unported license.

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The Journal of Immunology: 206 (3)
The Journal of Immunology
Vol. 206, Issue 3
1 Feb 2021
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Direct Antiviral Activity of IFN-Stimulated Genes Is Responsible for Resistance to Paramyxoviruses in ISG15-Deficient Cells
David Holthaus, Andri Vasou, Connor G. G. Bamford, Jelena Andrejeva, Christina Paulus, Richard E. Randall, John McLauchlan, David J. Hughes
The Journal of Immunology May 18, 2020, ji1901472; DOI: 10.4049/jimmunol.1901472

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Direct Antiviral Activity of IFN-Stimulated Genes Is Responsible for Resistance to Paramyxoviruses in ISG15-Deficient Cells
David Holthaus, Andri Vasou, Connor G. G. Bamford, Jelena Andrejeva, Christina Paulus, Richard E. Randall, John McLauchlan, David J. Hughes
The Journal of Immunology May 18, 2020, ji1901472; DOI: 10.4049/jimmunol.1901472
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Print ISSN 0022-1767        Online ISSN 1550-6606