One important factor that needs to be examined is the relationship of the reactivity of these OTU domains to species specificity of the viruses. Influenza B was found to inhibit the human but not the mouse ISG15ylation system [39] . The nairovirus OTUs appear to act by cleaving Ub and ISG15 from their respective conjugates, since mutations in the active site abolish activity [24] , and the OTUs are therefore active against both human and murine systems. However, there was a clear difference between the activity of the CCHFV and NSDV/GV OTUs in the murine ISG15ylation system used in this study. We know little of the ruminant equivalents of the Ubls, and it is possible that the OTUs of different viruses may be adapted to species differences in these modifying proteins which could lead in turn to differences in the species specificity of pathogenesis. It will be important to examine the actual level of modification of host cell proteins when these viruses are grown in cells from different hosts to establish whether there is any degree of correlation between OTU cleavage activity and host cell species.