Multiple genome segments determine virulence of bluetongue virus serotype 8

Janowicz, A., Caporale, M., Shaw, A., Gulletta, S., Di Gialleonardo, L., Ratinier, M. and Palmarini, M. (2015) Multiple genome segments determine virulence of bluetongue virus serotype 8. Journal of Virology, 89(10), pp. 5238-5249. (doi: 10.1128/JVI.00395-15) (PMID:25822026) (PMCID:PMC4442542)

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Bluetongue virus (BTV) causes bluetongue, a major hemorrhagic disease of ruminants. In order to investigate the molecular determinants of BTV virulence, we used a BTV8 strain minimally passaged in tissue culture (termed BTV8L in this study) and a derivative strain passaged extensively in tissue culture (BTV8H) in in vitro and in vivo studies. BTV8L was pathogenic in both IFNAR−/− mice and in sheep, while BTV8H was attenuated in both species. To identify genetic changes which led to BTV8H attenuation, we generated 34 reassortants between BTV8L and BTV8H. We found that partial attenuation of BTV8L in IFNAR−/− mice was achieved by simply replacing genomic segment 2 (Seg2, encoding VP2) or Seg10 (encoding NS3) with the BTV8H homologous segments. Fully attenuated viruses required at least two genome segments from BTV8H, including Seg2 with either Seg1 (encoding VP1), Seg6 (encoding VP6 and NS4), or Seg10 (encoding NS3). Conversely, full reversion of virulence of BTV8H required at least five genomic segments of BTV8L. We also demonstrated that BTV8H acquired an increased affinity for glycosaminoglycan receptors during passaging in cell culture due to mutations in its VP2 protein. Replication of BTV8H was relatively poor in interferon (IFN)-competent primary ovine endothelial cells compared to replication of BTV8L, and this phenotype was determined by several viral genomic segments, including Seg4 and Seg9. This study demonstrated that multiple viral proteins contribute to BTV8 virulence. VP2 and NS3 are primary determinants of BTV pathogenesis, but VP1, VP5, VP4, VP6, and VP7 also contribute to virulence.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Ratinier, Dr Maxime and Di Gialleonardo, Dr Luigina and Palmarini, Professor Massimo and Gulletta, Dr Salvatore and Caporale, Dr Marco and Shaw, Dr Andrew
Authors: Janowicz, A., Caporale, M., Shaw, A., Gulletta, S., Di Gialleonardo, L., Ratinier, M., and Palmarini, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Virology
Journal Abbr.:J. Virol.
Publisher:American Society for Microbiology
ISSN (Online):1098-5514
Copyright Holders:Copyright © 2015 Janowicz et al.
First Published:First published in Journal of General Virology 89(10):5238-5249
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
544121Phylogeography, transmission dynamics and pathogenesis of bluetongueMassimo PalmariniWellcome Trust (WELLCOME)092806/Z/10/ZMVLS III - CENTRE FOR VIRUS RESEARCH