Crimean-Congo hemorrhagic fever virus (CCHFV) is a ssRNA (-) nairovirus that produces fever, prostration, and severe hemorrhages in humans. Fatality rates associated with CCHFV range from 5- 80% based on phylogenetic variation of the virus, transmission route, and different treatment facilities. Originally identified in Russia and he Congo, CCHFV has rapidly spread across large sections of Europe, Asia, and Africa. Recently, U.S. citizen traffic has increased substantially to the regions endemic with CCHFV, specifically South Central Asia. As a result, there is a substantial risk for transmission of CCHFV and/or its tick vector to the United States. Intriguingly, CCHFV is not the only nairovirus that threatens the public. Nairobi Sheep Disease virus (NSDV) as well as nairoviruses Hazara, Dugbe and Erve can cause human disease of varying severity and economic distress. Currently, there is no vaccine or prophylactic available for treatment of CCHF or other any other nairovirus related diseases. Recent reports have identified a viral homologue of the ovarian tumor protease (vOTU) located within the nairovirus genome and implicated its possible involvement in down-regulation of the Interferon type 1 immune response through cleavage of post-translational modifying proteins ubiquitin (Ub) and Ub-like interferon-simulated gene 15 (ISG15). As a result, it has been suggested to be a virulence factor. This proposal will determine whether dual deubiquitinating and deISGylating activities are conserved functions of this subclass of proteases in vitro and in vivo. Additionally, these experiments will gain insight into their mechanism of recognition for Ub and ISG15 allowing greater predictability of currently unknown vOTUs. The proposal will also seek to evaluate a potential correlation between the in vitro activity/substrate specificity of these nairovirus vOTUs and overall virulence of the nairoviruses in question. The resulting information will also provide critical insight into the role of vOTUs ply in viruses that may ultimately have practicality in the development of prophylactics targeting vOTUs.

Public Health Relevance

Crimean-Congo hemorrhagic fever (CCHF), Thunderclap headaches, Hazara hemorrhagic fever, and Nairobi sheep disease, are dangerous emerging human and animal diseases that can potentially cause widespread health and economic devastation. The causative agents for these diseases are different forms of nairoviruses. Recently, nairoviruses have been suggested to share a conserved evasion mechanism that hinders the human innate immune response. This proposal serves to evaluate that mechanism's influence on virulence amongst diverse nairoviruses with an emphasis on the CCHF virus through synergetic in vitro, in cellulo and in vivo means. In doing so, this proposal will provide information on the practicality of developing selective and broad-based anti-viral treatments.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Virology - B Study Section (VIRB)
Program Officer
Repik, Patricia M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Georgia
Schools of Pharmacy
United States
Zip Code
Zivcec, Marko; Scholte, Florine E M; Spiropoulou, Christina F et al. (2016) Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus. Viruses 8:106
Spengler, Jessica R; Estrada-Peña, Agustín; Garrison, Aura R et al. (2016) A chronological review of experimental infection studies of the role of wild animals and livestock in the maintenance and transmission of Crimean-Congo hemorrhagic fever virus. Antiviral Res 135:31-47
Deaton, M K; Dzimianski, J V; Daczkowski, C M et al. (2016) Biochemical and Structural Insights into the Preference of Nairoviral DeISGylases for Interferon-Stimulated Gene Product 15 Originating from Certain Species. J Virol 90:8314-27
Spengler, Jessica R; Bergeron, Éric; Rollin, Pierre E (2016) Seroepidemiological Studies of Crimean-Congo Hemorrhagic Fever Virus in Domestic and Wild Animals. PLoS Negl Trop Dis 10:e0004210
Zivcec, Marko; Metcalfe, Maureen G; Albariño, César G et al. (2015) Assessment of Inhibitors of Pathogenic Crimean-Congo Hemorrhagic Fever Virus Strains Using Virus-Like Particles. PLoS Negl Trop Dis 9:e0004259
Eisenmesser, Elan Z; Capodagli, Glenn C; Armstrong, Geoffrey S et al. (2015) Inherent dynamics within the Crimean-Congo Hemorrhagic fever virus protease are localized to the same region as substrate interactions. Protein Sci 24:651-60
Spengler, Jessica R; Patel, Jenish R; Chakrabarti, Ayan K et al. (2015) RIG-I Mediates an Antiviral Response to Crimean-Congo Hemorrhagic Fever Virus. J Virol 89:10219-29
Bergeron, Éric; Zivcec, Marko; Chakrabarti, Ayan K et al. (2015) Recovery of Recombinant Crimean Congo Hemorrhagic Fever Virus Reveals a Function for Non-structural Glycoproteins Cleavage by Furin. PLoS Pathog 11:e1004879
Deaton, Michelle K; Spear, Allyn; Faaberg, Kay S et al. (2014) The vOTU domain of highly-pathogenic porcine reproductive and respiratory syndrome virus displays a differential substrate preference. Virology 454-455:247-53
Capodagli, Glenn C; Sedhom, Wafik G; Jackson, Mary et al. (2014) A noncompetitive inhibitor for Mycobacterium tuberculosis's class IIa fructose 1,6-bisphosphate aldolase. Biochemistry 53:202-13