Toscana Virus NSs Protein Inhibits the Induction of Type I Interferon by Interacting with RIG-I

Savellini, Gianni Gori; Valentini, Melissa; Cusi, Maria Grazia

doi:10.1128/jvi.03129-12

Cited by 43 publications

(51 citation statements)

References 43 publications

(59 reference statements)

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“…5). When expressed separately from their cognate viruses, both PTV and TOSV NSs proteins act as reasonably potent IFN antagonists (53,54), as also observed for the NSs protein of sandfly fever Sicilian virus (53,55). We observed a 10-fold increase in IFN production when A549 cells were infected with the NSs-deleted viruses, suggesting that UUKV NSs also plays a role in antagonizing the host cell IFN response.…”

Section: Discussionmentioning

confidence: 50%

“…As UUKV NSs localizes in the cytoplasm (57), like other phlebovirus NSs proteins, its mode of antagonizing the IFN response is expected to be different from that of RVFV. TOSV NSs inhibits the dimerization of IFN regulatory factor 3 (IRF-3), hence preventing its localization to the nucleus and the subsequent induction of the IFN-␤ promoter (52), and this is most likely because the protein inhibits the induction of type I IFN by targeting retinoic acidinducible gene I (RIG-I) for proteasomal degradation (54). In SFTSV-infected cells, NSs forms cytoplasmic structures termed viroplasm (58), which are believed to redistribute RIG-I signaling components in order to suppress IFN responses (49,59,60).…”

Section: Discussionmentioning

confidence: 99%

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Generation of Mutant Uukuniemi Viruses Lacking the Nonstructural Protein NSs by Reverse Genetics Indicates that NSs Is a Weak Interferon Antagonist

Rezelj

Överby

Elliott

2015

J Virol

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Uukuniemi virus (UUKV) is a tick-borne member of the Phlebovirus genus (family Bunyaviridae) and has been widely used as a safe laboratory model to study aspects of bunyavirus replication. Recently, a number of new tick-borne phleboviruses have been discovered, some of which, like severe fever with thrombocytopenia syndrome virus and Heartland virus, are highly pathogenic in humans. UUKV could now serve as a useful comparator to understand the molecular basis for the different pathogenicities of these related viruses. We established a reverse-genetics system to recover UUKV entirely from cDNA clones. We generated two recombinant viruses, one in which the nonstructural protein NSs open reading frame was deleted from the S segment and one in which the NSs gene was replaced with green fluorescent protein (GFP), allowing convenient visualization of viral infection. We show that the UUKV NSs protein acts as a weak interferon antagonist in human cells but that it is unable to completely counteract the interferon response, which could serve as an explanation for its inability to cause disease in humans. IMPORTANCE Uukuniemi virus (UUKV) is a tick-borne phlebovirus that is apathogenic for humans and has been used as a convenient model to investigate aspects of phlebovirus replication. Recently, new tick-borne phleboviruses have emerged, such as severe fever with thrombocytopenia syndrome virus in China and Heartland virus in the UnitedStates, that are highly pathogenic, and UUKV will now serve as a comparator to aid in the understanding of the molecular basis for the virulence of these new viruses. To help such investigations, we have developed a reverse-genetics system for UUKV that permits manipulation of the viral genome. We generated viruses lacking the nonstructural protein NSs and show that UUKV NSs is a weak interferon antagonist. In addition, we created a virus that expresses GFP and thus allows convenient monitoring of virus replication. These new tools represent a significant advance in the study of tick-borne phleboviruses. The Bunyaviridae are the largest grouping of RNA viruses, comprising Ͼ350 members. The family includes a wide range of enveloped, single-stranded RNA viruses with tripartite genomes of negative-sense or ambisense polarity. The Phlebovirus genus contains 70 viruses divided into two groups: the sandfly fever group, transmitted mainly by phlebotomines and mosquitoes, and the Uukuniemi-like virus group, transmitted by ticks. Uukuniemi virus (UUKV) itself was originally isolated in 1964 from an Ixodes ricinus tick in Finland (1). UUKV has served as a prototype tick-borne phlebovirus for many years and has aided in advances in bunyavirus structural and architectural determination (2-4), bunyavirus glycoprotein studies (5-9), and studies of bunyavirus entry into mammalian cells (10-12).Like other phleboviruses, the three UUKV genome segments, designated small (S), medium (M), and large (L), are found in the form of ribonucleoprotein (RNP) complexes in association with the nucleocapsid (N)...

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Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Generation of Mutant Uukuniemi Viruses Lacking the Nonstructural Protein NSs by Reverse Genetics Indicates that NSs Is a Weak Interferon Antagonist

Rezelj

Överby

Elliott

2015

J Virol

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“…The signal transduction between mitochondrial antiviral signaling protein and TBK1 is mediated by mediator of IRF3 activation (MITA). However, LGP2, lacking the two caspase recruitment domains in the N terminus, is believed to act as a negative regulator of the RLR signaling pathway (3)(4)(5)(6)(7). Recently, several reports demonstrated that a functional RLR signaling pathway also exists in fish, suggesting that the RLRmediated antiviral pathway is conserved from lower vertebrate to mammals (8)(9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

IFN Regulatory Factor 10 Is a Negative Regulator of the IFN Responses in Fish

Hong

et al. 2014

The Journal of Immunology

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IFN regulatory factor (IRF) 10 belongs to the IRF family and exists exclusively in birds and fish. Most IRFs have been identified as critical regulators in the IFN responses in both fish and mammals; however, the role of IRF10 is unclear. In this study, we identified IRF10 in zebrafish (Danio rerio) and found that it serves as a negative regulator to balance the innate antiviral immune responses. Zebrafish IRF10 (DrIRF10) was induced by intracellular polyinosinic:polycytidylic acid in ZF4 (zebrafish embryo fibroblast-like) cells. DrIRF10 inhibited the activation of zebrafish IFN1 (DrIFN1) and DrIFN3 promoters in epithelioma papulosum cyprinid cells in the presence or absence of polyinosinic:polycytidylic acid stimulation through direct interaction with the IFN promoters, and this inhibition was also shown to block IFN signaling. Overexpression of DrIRF10 was able to abolish the induction of DrIFN1 and DrIFN3 mediated by the retinoic acid–inducible gene I–like receptors. In addition, functional domain analysis of DrIRF10 showed that either the DNA binding domain or the IRF association domain is sufficient for its inhibitory activity for IFN signaling. Lastly, overexpression of DrIRF10 decreased the transcription level of several IFN-stimulated genes, resulting in the susceptibility of host cells to spring viremia of carp virus infection. Collectively, these data suggest that DrIRF10 inhibits the expression of DrIFN1 and DrIFN3 to avoid an excessive immune response, a unique regulation mechanism of the IFN responses in lower vertebrates.

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“…28,29,32 We assume that RVFV NSs functions, such as general transcription suppression, PKR degradation, or IFN-b suppression, coordinately support efficient RVFV replication and spread in liver tissues, and thus, the spreads of rZH501-TOSNSs and rZH501-SFSNSs were more restricted than parental rZH501 in mouse livers.…”

Section: Discussionmentioning

confidence: 99%

“…Toscana virus (TOSV), sandfly fever Sicilian virus (SFSV), or Punta Toro virus (PTV) Adames strain (PTA) are known to inhibit the upregulation of IFN-b gene. [28][29][30][31] In addition, TOSV NSs also promotes the degradation of PKR. 32 The MP-12 encoding TOSV NSs (rMP12-TOSNSs), however, showed increased viral encephalitis in vaccinated mice (30% or more), compared to parental MP-12, which causes encephalitis in up to 5% of mice.…”

Section: Introductionmentioning

confidence: 99%

Attenuation of pathogenic Rift Valley fever virus strain through the chimeric S-segment encoding sandfly fever phlebovirus NSs or a dominant-negative PKR

et al. 2016

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Rift Valley fever is a mosquito-borne zoonotic disease affecting ruminants and humans. Rift Valley fever virus (RVFV: family Bunyaviridae, genus Phlebovirus) causes abortions and fetal malformations in ruminants, and hemorrhagic fever, encephalitis, or retinitis in humans. The live-attenuated MP-12 vaccine is conditionally licensed for veterinary use in the US. However, this vaccine lacks a marker for the differentiation of vaccinated from infected animals (DIVA). NSs gene is dispensable for RVFV replication, and thus, rMP-12 strains lacking NSs gene is applicable to monitor vaccinated animals. However, the immunogenicity of MP-12 lacking NSs was not as high as parental MP-12. Thus, chimeric MP-12 strains encoding NSs from either Toscana virus (TOSV), sandfly fever Sicilian virus (SFSV) or Punta Toro virus Adames strain (PTA) were characterized previously. Although chimeric MP-12 strains are highly immunogenic, the attenuation through the S-segment remains unknown. Using pathogenic ZH501 strain, we aimed to demonstrate the attenuation of ZH501 strain through chimeric S-segment encoding either the NSs of TOSV, SFSV, PTA, or Punta Toro virus Balliet strain (PTB). In addition, we characterized rZH501 encoding a human dominant-negative PKR (PKRDE7), which also enhances the immunogenicity of MP-12. Study done on mice revealed that attenuation of rZH501 occurred through the S-segment encoding either PKRDE7 or SFSV NSs. However, rZH501 encoding either TOSV, PTA, or PTB NSs in the S-segment uniformly caused lethal encephalitis. Our results indicated that the S-segments encoding PKRDE7 or SFSV NSs are attenuated and thus applicable toward next generation MP-12 vaccine candidates that encode a DIVA marker.

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Toscana Virus NSs Protein Inhibits the Induction of Type I Interferon by Interacting with RIG-I

Cited by 43 publications

References 43 publications

Generation of Mutant Uukuniemi Viruses Lacking the Nonstructural Protein NSs by Reverse Genetics Indicates that NSs Is a Weak Interferon Antagonist

Generation of Mutant Uukuniemi Viruses Lacking the Nonstructural Protein NSs by Reverse Genetics Indicates that NSs Is a Weak Interferon Antagonist

IFN Regulatory Factor 10 Is a Negative Regulator of the IFN Responses in Fish

Attenuation of pathogenic Rift Valley fever virus strain through the chimeric S-segment encoding sandfly fever phlebovirus NSs or a dominant-negative PKR

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