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Direct antiviral activity of interferon stimulated genes is responsible for resistance to paramyxoviruses in ISG15-deficient cells

David Holthaus, View ORCID ProfileAndri Vasou, View ORCID ProfileConnor G. G. Bamford, Jelena Andrejeva, View ORCID ProfileChristina Paulus, View ORCID ProfileRichard E. Randall, View ORCID ProfileJohn McLauchlan, View ORCID ProfileDavid J. Hughes
doi: https://doi.org/10.1101/2019.12.12.873919
David Holthaus
1Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St Andrews, United Kingdom
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Andri Vasou
1Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St Andrews, United Kingdom
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Connor G. G. Bamford
2MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
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Jelena Andrejeva
1Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St Andrews, United Kingdom
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Christina Paulus
1Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St Andrews, United Kingdom
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  • ORCID record for Christina Paulus
Richard E. Randall
1Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St Andrews, United Kingdom
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John McLauchlan
2MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
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David J. Hughes
1Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St Andrews, United Kingdom
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  • ORCID record for David J. Hughes
  • For correspondence: djh25@st-andrews.ac.uk
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Abstract

Interferons (IFNs), produced during viral infections, induce the expression of hundreds of IFN- stimulated genes (ISGs). Some ISGs have specific antiviral activity while others regulate the cellular response. Besides functioning as an antiviral effector, IFN-stimulated gene 15 (ISG15) is a negative regulator of IFN signalling and inherited ISG15-deficiency leads to autoinflammatory interferonopathies where 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 pre-treated 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 non-permissive due to 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 (PIV5). Knockdown of IFIT1 restored PIV5 infection in IFN-α-pre-treated 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 pre-treated with IFN-α for longer times, presumably due to inhibition of protein synthesis. These data show that the cause of virus resistance is two-fold; ISG15-deficiency leads to the ‘early’ over-expression of specific antiviral ISGs, but the later response is dominated by an unanticipated, ISG15- dependent, loss of translational control.

Key points Cell culture model of ISG15-deficiency replicate findings in ISG15-/- patient cells

Cause of resistance in ISG15-/- cells differs depending on duration of IFN treatment

ISG15-/- patients without serious viral disease don’t prove ISGylation is unimportant

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted April 21, 2020.
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Direct antiviral activity of interferon 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
bioRxiv 2019.12.12.873919; doi: https://doi.org/10.1101/2019.12.12.873919
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Direct antiviral activity of interferon 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
bioRxiv 2019.12.12.873919; doi: https://doi.org/10.1101/2019.12.12.873919

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