Activation of interferon-γ signalling by SFTS virus NSs protein Zi-Wei Ye1, Vidyanath Chudhary2, Jasper Fuk-Woo Chan1, Dong-Yan Jin2* 1Department of Microbiology, The University of Hong Kong, Hong Kong; 2School of Biomedical Sciences, The University of Hong Kong, Hong Kong *Corresponding Author
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease presented with severe acute fever, leukocytopenia, thrombocytopenia and other symptoms. The causative agent, SFTS virus (SFTSV), is a tick-born phlebovirus, which poses a constant threat to public health in China and elsewhere. WHO has ranked SFTSV as one of the most dangerous emerging infectious diseases, in the category which also includes Zika virus. Unlike Zika virus, SFTSV is severely understudied and our understanding on SFTS and SFTSV is still very limited, and neither antiviral drugs nor vaccines are available for SFTSV. Understanding the pathogenesis and immunopathogenesis of SFTSV infection will facilitate the development of new strategies and approaches to combat SFTSV. In this study, we demonstrated that SFTSV NSs protein augments IFN-γ signalling, as shown by the induction of IFN-γ-stimulated genes, IP10, IRF1, MCP1, PD-L1 and PD-L2. By screening a panel of SFTSV proteins (NSs, NP, Gc, Gn and L) for potentiation of target gene activation by IFN-γ, we found that mRNA transcript of IRF1 gene, primarily induced by IFN-γ, was upregulated by NSs protein. Similarly, NSs highly induced mRNA transcripts of IP10, MCP1, PD-L1 and PD-L2 in IFN-γ-treated cells. As IFN-γ signalling is regulated by STAT1 phosphorylation at two major sites (Y701 and S727) and modification at both sites is required for full activation of STAT1, we analysed the association between STAT1 phosphorylation and NSs potentiation of IFN-γ signalling. Strikingly, phosphorylation of STAT1 at Y701 and S727 positions was detected to be higher in the presence of IFN-γ by Western blotting, which indicated that NSs acts mainly on IFN-γ-induced STAT1 phosphorylation. Finally, IFN-γ promoted SFTSV replication through the induction of IP10 and PD-L1. Further investigations are required to elucidate how activation of PD-L1 immune checkpoint might contribute to SFTSV pathogenesis. Collectively, our work has characterised IFN-γ-mediated enhancement of SFTSV replication and the mechanism of SFTSV-induced augmentation of IFN-γ signalling, which will guide the development of new preventive and therapeutic measures.
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