ID: 107: Inhibition of type I IFN induction by Sandfly fever Sicilian virus virulence factor NSs

Abstract

Phleboviruses are a group of emerging viruses with a wide spectrum of virulence: For example, Rift Valley Fever virus (RVFV) is highly pathogenic, whereas Sandfly fever Sicilian virus (SFSV) causes intermediate pathogenicity. The major virulence factor is the non-structural protein NSs, a suppressor of the type I interferon (IFN) system. While the NSs protein of highly pathogenic RVFV inhibits global host cell transcription via sequestration and degradation of the TFIIH subunits p44 and p62, respectively, the mode of action of the NSs protein of intermediately pathogenic SFSV has remained elusive. We therefore aimed to characterize the IFN-inhibitory function employed by the NSs of SFSV. Using mass spectrometry, our group has identified multiple candidate host interactors, among them interferon regulatory factor 3 (IRF3). Indeed, co-immunoprecipitation confirmed the interaction of SFSV NSs with IRF3, but not with other IRF family members like IRF2, IRF5 and IRF9. Furthermore, SFSV NSs specifically abrogated IRF3 activation and thus IFN- β promoter activity, but not general host cell transcription. Hence, SFSV encodes a NSs protein that efficiently inhibits the induction of type I IFN. Different to the highly pathogenic RVFV, which induces a general host transcription shutoff, however, SFSV specifically targets IRF3-dependent IFN promoter activation. Although RVFV and SFSV are highly related, their NSs proteins display remarkably diverse strategies of counteracting the type I IFN system. Possibly, the quality of NSs-host factor interactions correlates with the virulence levels of phleboviruses.