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Severe Fever with Thrombocytopenia Syndrome (SFTS) virus is an emerging tick-borne Phlebovirus isolated from patients presenting with hemorrhagic manifestations. Case fatality rates of 12-50% have been reported. Limited information regarding SFTS virus pathogenesis is known. Inhibition of interferon (IFN) responses by SFTS virus NSs has been shown to correlate with the relocation of RIG-I signaling proteins into early endosomal-derived cytoplasmic structures positive for SFTS virus NSs. Moreover, ubiquitin, an important post-translational modifier required for initiation of the RIG-I signaling cascade, also localizes to SFTS virus NSs cytoplasmic structures. Recently, through Live Cell Imaging of a stable cell line expressing the SFTS virus NSs-mCherry, we observed secretion of some of the SFTS virus NSs-positive structures into the extracellular space. Concurrently, ultrastructural analysis of secreted structures from SFTS virus infected cells revealed that 50% harbored viral-like particles. These secreted structures were also proven to 1) mediate dissemination of SFTS virus and 2) initiate a successful SFTS virus infection even in the presence of neutralizing antibodies. Additionally, proteomic analysis of cytoplasmic SFTS virus NSs structures from infected cells detected components of the 26S proteasome within these structures and transient expression of the SFTS virus NSs resulted in decreased levels of ubiquitinated proteins. Furthermore, SFTS virus infection leads to the reduction of RIG-I and TBK-1 expression, which were recovered when the Ubiquitin-Proteasomal Pathway was inhibited using MG-132. Lastly, we observed that mutation of ubiquitination sites of RIG-I and TBK-1 prevented and reduced the interaction with SFTS virus NSs, respectively. Altogether, our study suggests a novel mechanism for dissemination and innate immune evasion not previously described for tick-borne phleboviruses.



Bunyavirus, Phlebovirus, tick-borne, NSs, RIG-I, TBK-1, ubiquitin, extracellular vesicles