Assessment of deubiquitinating and deISGylating activity; specificity motifs amon

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DESCRIPTION (provided by applicant): Crimean-Congo hemorrhagic fever (CCHF) virus is a ssRNA (-) nairovirus that produces fever, prostration, and severe hemorrhages in humans. Fatality rates for CCHF range from 5-70% based on phylogenetic variation of the virus, transmission route, and different treatment facilities. Originally identified in Russia and the Congo, CCHF has rapidly spread across large sections of Europe, Asia, and Africa. Recently, U.S. citizen traffic has increased substantially to the regions affected by CCHF, specifically South Central Asia. As a result, there is a substantial risk for transmission of CCHF and/or its tick vector to the U.S. Currently, there is no vaccine or prophylactic available for treatment of CCHF. Recent reports have identified a viral homologue of the ovarian tumor protease (vOTU) 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-stimulated gene 15 (ISG15). Additionally, a low sequence homology homologue of vOTU has been suggested to perform a similar role in the economically devastating ssRNA (+) arteriviruses, Porcine Respiratory and Reproduction Syndrome and Equine arteritis. This proposal will determine whether deubiquitinating and deISGylating activity is conserved function of this subclass of protease as well as gain insight into their mechanism of recognition for Ub and ISG15. The resulting information will provide insight into the function of vOTUs in different viruses that may ultimately have practicality in the development of prophylactics targeting vOTUs. PUBLIC HEALTH RELEVANCE: Crimean-Congo hemorrhagic Fever and Porcine Respiratory and Reproductive Syndrome are dangerous emerging human and animal diseases that can potentially cause widespread health and economic devastation. These diseases originate from two divergent viral families that have been suggested to share a conserved evasion mechanism that hinders human innate immune response. This proposal serves to evaluate that mechanism in order to provide information on the practicality of developing a broad anti-viral treatment.