Development of Molecular Host-Centric Methodology Seeking to Pinpoint Reservoirs of Nairoviruses by Interferon-Stimulated Gene Product 15

Nairoviruses, tick-borne viruses from the Bunyaviridae family, pose persistent and significant threats to human health. While the most notable is Crimean-Congo hemorrhagic fever virus (CCHFV), which possesses a fatality rate pushing 30%, other nairoviruses are establishing themselves in our viromes including Pacific Coast tick nairovirus (PCTN) and Songling virus (SGLV). To thwart host antiviral immune response, specifically reversing the post-translational modifications of interferon-stimulated gene product 15 (ISG15) after infection, nairoviruses encode for and utilize an ovarian tumor domain protease (OTU) capable of deISGylation. The fact that ISG15 structure and sequence is hardly conserved between species, coupled with previous studies demonstrating diverse OTU preferences for certain ISG15s, pinpoints these two as key subjects of disease prevention due to possible variations in interaction. To gain a broader understanding of nairovirus OTU-ISG15 interface and identify possible host carriers, a high-throughput method of obtaining binding kinetic data was developed which employed bio-layer interferometry (BLI). ~72 interactions between vOTUs and ISG15 were examined, which revealed significant differences for nairovirus OTU binding preferences. CCHF and PCTN vOTUs put on robust displays of binding, while SGLV vOTU showcased more specificity for which ISG15s it bound to. These insights serve to be progress and contributions towards building a larger biosurveillance tool ultimately unveiling pivotal animal reservoirs of nairoviruses.