Multi-Faceted Proteomic Characterization of Host Protein Complement of Rift Valley Fever Virus Virions and Identification of Specific Heat Shock Proteins, Including HSP90, as Important Viral Host Factors

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dc.contributor.authorNuss, Jonathan E.
dc.contributor.authorKehn-Hall, Kylene
dc.contributor.authorBenedict, Ashwini
dc.contributor.authorCostantino, Julie
dc.contributor.authorWard, Michael
dc.contributor.authorPeyser, Brian D.
dc.contributor.authorRetterer, Cary J.
dc.contributor.authorTressler, Lyal E.
dc.contributor.authorWanner, Laura M.
dc.contributor.authorMcGovern, Hugh F.
dc.contributor.authorZaidi, Anum
dc.contributor.authorAnthony, Scott M.
dc.contributor.authorKota, Krishna P.
dc.contributor.authorBavari, Sina
dc.contributor.authorHakami, Ramin M.
dc.date.accessioned2015-10-13T18:55:39Z
dc.date.available2015-10-13T18:55:39Z
dc.date.issued2014-05-08
dc.description.abstractRift Valley fever is a potentially fatal disease of humans and domestic animals caused by Rift Valley fever virus (RVFV). Infection with RVFV in ruminants can cause near 100% abortion rates and recent outbreaks in naïve human populations have suggested case fatality rates of greater than thirty percent. To elucidate the roles that host proteins play during RVFV infection, proteomic analysis of RVFV virions was conducted using complementary analytical approaches, followed by functional validation studies of select identified host factors. Coupling the more traditional Gel LC/MS/MS approach (SDS PAGE followed by liquid chromatography tandem mass spectrometry) with an alternative technique that preserves protein complexes allowed the protein complement of these viral particles to be thoroughly examined. In addition to viral proteins present within the virions and virion-associated host proteins, multiple macromolecular complexes were identified. Bioinformatic analysis showed that host chaperones were among over-represented protein families associated with virions, and functional experiments using siRNA gene silencing and small molecule inhibitors identified several of these heat shock proteins, including heat shock protein 90 (HSP90), as important viral host factors. Further analysis indicated that HSP inhibition effects occur during the replication/transcription phase of the virus life cycle, leading to significant lowering of viral titers without compromising the functional capacity of released virions. Overall, these studies provide much needed further insight into interactions between RVFV and host cells, increasing our understanding of the infection process and suggesting novel strategies for anti-viral development. In particular, considering that several HSP90 inhibitors have been advancing through clinical trials for cancer treatment, these results also highlight the exciting potential of repurposing HSP90 inhibitors to treat RVF.
dc.description.sponsorshipThis research was supported by funding awarded to R.M.H. by the U.S. Army Medical Research and Materiel Command (MRMC) (W81XWH-11-P-0310) and George Mason University, and by a grant awarded to S.B. from the Defense Threat Reduction Agency Transformational Medical Technologies [TMTI0048_09_RD_T]. Publication of this article was funded in part by the George Mason University Libraries Open Access Publishing Fund
dc.identifier.citationNuss JE, Kehn-Hall K, Benedict A, Costantino J, Ward M, Peyser BD, et al. (2014) Multi-Faceted Proteomic Characterization of Host Protein Complement of Rift Valley Fever Virus Virions and Identification of Specific Heat Shock Proteins, Including HSP90, as Important Viral Host Factors. PLoS ONE 9(5): e93483. doi:10.1371/journal.pone.0093483
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0093483
dc.identifier.urihttps://hdl.handle.net/1920/9943
dc.language.isoen_US
dc.publisherPublic Library of Science
dc.rightsAttribution 3.0 United States
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/us/
dc.subjectRift Valley Fever virus
dc.subjectSmall interfering RNAs
dc.subjectVirions
dc.subjectHeat shock response
dc.subjectChaperone proteins
dc.subjectMembrane proteins
dc.subjectProtein interaction networks
dc.subjectDatabase searching
dc.titleMulti-Faceted Proteomic Characterization of Host Protein Complement of Rift Valley Fever Virus Virions and Identification of Specific Heat Shock Proteins, Including HSP90, as Important Viral Host Factors
dc.typeArticle

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