Interferon-stimulated gene (ISG)-expression screening reveals the specific antibunyaviral activity of ISG20

Feng, J. et al. (2018) Interferon-stimulated gene (ISG)-expression screening reveals the specific antibunyaviral activity of ISG20. Journal of Virology, 92(13), e02140-17. (doi: 10.1128/JVI.02140-17) (PMID:29695422) (PMCID:PMC6002717)

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Bunyaviruses pose a significant threat to human health, prosperity and food security. In response to viral infections, interferons (IFNs) upregulate the expression of hundreds of interferon stimulated genes (ISGs) whose cumulative action can potently inhibit the replication of bunyaviruses. We used a flow cytometry-based method to screen the ability of ∼500 unique ISGs from humans and rhesus macaques to inhibit the replication of Bunyamwera orthobunyavirus (BUNV), the prototype of both the Peribunyaviridae family and Bunyavirales order. Candidates possessing antibunyaviral activity were further examined using a panel of divergent bunyaviruses. Interestingly, one candidate, ISG20, exhibited potent antibunyaviral activity against most viruses examined from the Peribunyaviridae, Hantaviridae and Nairoviridae families, whereas phleboviruses (Phenuiviridae) largely escaped inhibition. Similar to other viruses known to be targeted by ISG20, the antibunyaviral activity of ISG20 is dependent upon its functional ribonuclease activity. Through use of an infectious VLP assay (based on the BUNV minigenome system), we confirmed that gene expression from all 3 viral segments is strongly inhibited by ISG20. Using in vitro evolution, we generated a substantially ISG20-resistant BUNV and mapped the determinants of ISG20 sensitivity/resistance. Taken together, we report that ISG20 is a broad and potent antibunyaviral factor yet some bunyaviruses are remarkably ISG20 resistant. Thus, ISG20 sensitivity/resistance could influence the pathogenesis of bunyaviruses, many of which are emerging viruses of clinical or veterinary significance.

Item Type:Articles
Additional Information:NIH grant NIH NIAID R01-AI091707 (to C.M.R) is acknowledged. J.F. was supported by the China Scholarship Council (CSC) and the University of Glasgow.
Glasgow Author(s) Enlighten ID:Wickenhagen, Mr Arthur and Elliott, Professor Richard and Feng, Junjie and Koudriakova, Elina and Shi, Dr Xiaohong and Brennan, Dr Benjamin and Rihn, Dr Suzannah and Turnbull, Dr Matthew and Wilson, Professor Sam and Shaw, Dr Andrew and Kreher, Dr Felix and Rezelj, Veronica Valentina
Authors: Feng, J., Wickenhagen, A., Turnbull, M. L., Rezelj, V. V., Kreher, F., Tilston-Lunel, N. L., Slack, G. S., Brennan, B., Koudriakova, E., Shaw, A. E., Rihn, S. J., Rice, C. M., Bieniasz, P. D., Elliott, R. M., Shi, X., and Wilson, S. J.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:Journal of Virology
Publisher:American Society for Microbiology
ISSN (Online):1098-5514
Published Online:25 April 2018
Copyright Holders:Copyright © 2018 Feng et al.
First Published:First published in Journal of Virology 92(13): e02140-17
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
618831Identifying and characterising antiretroviral interferon stimulated genes (ISGs)Sam WilsonMedical Research Council (MRC)MR/K024752/1MVLS III - CENTRE FOR VIRUS RESEARCH
635361Molecular analyses of arbovirus-host interactionsMassimo PalmariniWellcome Trust (WELLCOTR)099220/B/12/ZMVLS III - CENTRE FOR VIRUS RESEARCH