Phleboviruses versus the Type I/III Interferon Response: How Sandfly Fever Sicilian Virus NSs Tackles Interferon Induction and PKR-Mediated Restriction
Phleboviruses (order Bunyavirales, family Phenuiviridae) are arthropod-borne viruses that are emerging globally due to the geographic expansion of long-known members and the identification of numerous novel ones. They span a wide spectrum of virulence, comprising clinically inapparent infection, feb...
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|Summary:||Phleboviruses (order Bunyavirales, family Phenuiviridae) are arthropod-borne viruses that are emerging globally due to the geographic expansion of long-known members and the identification of numerous novel ones. They span a wide spectrum of virulence, comprising clinically inapparent infection, febrile disease, encephalitis, up to severe haemorrhagic fever and multiorgan failure – with novel isolates including both highly virulent members and abundant others with as yet unknown disease potential. Rift Valley fever virus (RVFV), a long-known member, is highly pathogenic for humans and livestock. Thus, RVFV has been subject to extensive molecular characterization, which established the phleboviral non-structural protein NSs as antagonist of the antiviral interferon (IFN) system and main virulence factor in the mammalian host. Sandfly fever Sicilian virus (SFSV), on the other hand, was identified as causative agent of ‘sandfly fever’, a self-limited febrile disease, during World War II. Nowadays, SFSV is one of the geographically most widespread phleboviruses, causing disease mainly in immunologically naïve military troops and travellers. Although SFSV has been thoroughly characterized with regard to its clinical picture, its interaction with the mammalian host remained almost entirely elusive on the molecular level.
In this work, we thus elucidated the molecular mechanisms with which the NSs protein of SFSV counteracts the interferon system. We identified that SFSV NSs dampened the induction of both type I and III interferons by specifically masking the DNA-binding domain of the transcription factor interferonregulatory factor 3 (IRF3). Despite IRF3 inhibition, however, SFSV did not fully abrogate IFN induction, leading to IFN-dependent upregulation of related transcription factor IRF7, which was not affected by SFSV NSs and fostered IFN induction. Additionally, SFSV NSs completely failed to impede IFN signalling, resulting in substantial expression of anti-phleboviral IFN-stimulated genes (ISGs). Thus, SFSV NSs appears to be a modulator rather than a full-blown antagonist of the IFN system.
Further, protein kinase R (PKR) possesses a strong restrictive activity towards phleboviruses due to the phosphorylation of its substrate eukaryotic elongation factor 2α (eIF2α) and the ensuing block of protein synthesis. Surprisingly, we found that the NSs protein of SFSV conferred PKR resistance and boosted translation without affecting the activation of PKR or the phosphorylation state of eIF2α. Instead, SFSV NSs targeted eIF2B, the central regulatory hub of the integrated stress response (ISR), further downstream. Of note, as previously characterized viral PKR antagonists all act at the levels of PKR activation and eIF2α phosphorylation, targeting of eIF2B by SFSV NSs represented a novel viral evasion strategy.
Interestingly, a common theme emerged during our studies: Highly virulent RVFV, on the one hand, utilizes its NSs to induce the degradation of target host factors via the proteasome, thereby acting in a catalytic mode. Furthermore, it establishes a global block of host gene expression to evade the IFN system. The NSs of mildly virulent SFSV, on the other hand, does not affect the expression levels of its host targets, but rather acts in a very specific and stoichiometric manner for both the inhibition of IFN induction and PKR evasion. Given its importance as exclusive phleboviral IFN antagonist, the NSs protein has been speculated to constitute a correlate of virulence. Our data on SFSV NSs support this hypothesis and argue for the characterization of the NSs proteins of novel phleboviruses with respect to their capacity to inhibit IFN induction, IFN signalling, and PKR activity in order to better estimate their potential to induce disease.|
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