Figure 9.

Model for the disruption of type I and III IFN signaling by HRTV and HNSs, compared with SFTSV and SNSs. Type I and III IFNs use two different cell surface receptor complexes (broadly expressed IFNAR1/IFNAR2 for type I IFNs and tissue-specifically distributed IFNLR1/IL-10R2 for type III IFNs) and then direct the similar JAK–STAT antiviral signaling. First, binding of type I and III IFNs to their respective receptors initiates the activation of JAKs. Then the JAKs activate STAT1 and STAT2 by phosphorylation, resulting in nuclear translocation of the transcription factors and subsequent induction of hundreds of antiviral ISGs. SFTSV infection or SNSs expression by transient transfection can inhibit the phosphorylation of STAT2 and the nuclear translocation of both STAT2 and STAT1, yielding similar inhibitory effects on STAT2 and STAT1 actions. In comparison, although like SNSs, HNSs also functions as an antagonist of type I and III IFN signaling, it exclusively blocks the activities of STAT2. Consistently, STAT2 phosphorylation and nuclear accumulation can be impeded in the context of HRTV infection. However, interestingly, HRTV infection also can significantly suppress STAT1 activation and nuclear translocation, albeit to a lesser degree, as an additional strategy for the immune evasion. Together, the blockade of both STAT2 and STAT1 actions by HRTV likely leads to a more radical subversion of type I and III IFN signaling. These findings highlight the functional conservativeness and mechanism differentiation of these related emerging viruses and their NSs proteins. IFNAR, IFN-α receptor; IFNLR, IFN-λ receptor; IL-10R, IL-10 receptor.