Surtees, R, Dowall, SD, Shaw, A et al. (7 more authors) (2016) Heat Shock Protein 70 family members interact with Crimean-Congo hemorrhagic fever virus and Hazara virus nucleocapsid proteins and perform a functional role in the nairovirus replication cycle. Journal of Virology, 90 (20). pp. 9305-9316. ISSN 0022-538X
Abstract
The Nairovirus genus of the Bunyaviridae family contains serious human and animal pathogens classified within multiple serogroups and species. Of these serogroups, the Crimean-Congo hemorrhagic fever virus (CCHFV) serogroup comprises sole members CCHFV and Hazara virus (HAZV). CCHFV is an emerging zoonotic virus that causes often-fatal hemorrhagic fever in infected humans for which preventative or therapeutic strategies are not available. In contrast HAZV is non-pathogenic to humans, and thus represents an excellent model to study aspects of CCHFV biology under more accessible biological containment. The three RNA segments that form the nairovirus genome are encapsidated by the viral nucleocapsid protein (N) to form ribonucleoprotein (RNP) complexes that are substrates for RNA synthesis and packaging into virus particles. We used quantitative proteomics to identify cellular interaction partners of CCHFV N, and identified robust interactions with cellular chaperones. These interactions were validated using immunological methods, and the specific interaction between native CCHFV N and cellular chaperones of the HSP70 family was confirmed during live CCHFV infection. Using infectious HAZV we showed for the first time that the nairovirus N-HSP70 association was maintained within both infected cells and virus particles, where N is assembled as RNPs. Reduction of active HSP70 levels in cells using small molecule inhibitors significantly reduced HAZV titres, and a model for chaperone function in the context of high genetic variability is proposed. These results suggest chaperones of the HSP70 family are required for nairovirus replication and thus represent a genetically stable cellular therapeutic target for preventing nairovirus-mediated disease.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 Surtees et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Crystallography (Leeds) |
Funding Information: | Funder Grant number Royal Society UF100419 Royal Society RG110306 Royal Society Not Known British Lung Foundation PPRG15-17 |
Depositing User: | Symplectic Publications |
Date Deposited: | 14 Jul 2016 15:22 |
Last Modified: | 22 Feb 2018 01:23 |
Published Version: | http://dx.doi.org/10.1128/JVI.00661-16 |
Status: | Published |
Publisher: | American Society for Microbiology |
Identification Number: | 10.1128/JVI.00661-16 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:102434 |