Origin of the innate immunity suppression caused by nairovirus' protease activity

Summary/Abstract 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 the Congo, CCHFV has rapidly spread across large sections of Europe, Asia, and Africa. Recently, CCHFV has illustrated its continued ability to spread into previously naive regions. At the same time, 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 Issyk-kul, Dugbe and Erve can cause human disease of varying severity and economic distress. There is no vaccine or prophylactic currently available for treatment of CCHF or any other nairovirus related disease. Reports have identified a viral homologue of the ovarian tumor protease (vOTU) located within the nairovirus genome. Recently, vOTUs' ability to reverse post-translational modification by proteins ubiquitin (Ub) and Ub-like interferon-simulated gene 15 (ISG15) on a narrow subset of host pathways has been illustrated to be critical to pathogenesis. Also, vOTUs from CCHFV and other nairoviruses have been found to be sensitive to species-species variations in ISG15 and their specificity includes at least the species that disease is most prominently identified. This proposal will determine the identity of specific host proteins within those pathways targeted by vOTUs. This will enable therapeutic approaches that protect, or elevate, specific host inhibitory factors for these viruses. The proposal will also seek to evaluate the correlation between the in vitro activity/substrate species-specificity of these nairovirus vOTUs and overall virulence and zoonotic range of the nairoviruses in question. Additionally, the efficacy of using CCHFV vaccine candidates with altered CCHF vOTU functions will be assessed. Together, the resulting information will provide critical insight into the role of vOTUs play in pathogenesis and host restriction as well as advance the development of prophylactics targeting vOTUs.