Viperin is an important host restriction factor in control of Zika virus infection

Hoek, Kylie H. Van der; Eyre, Nicholas S.; Shue, Byron; Khantisitthiporn, Onruedee; Glab-Ampi, Kittirat; Carr, Jillian M.; Gartner, Matthew J.; Jolly, Lachlan A.; Thomas, Paul Q.; Adikusuma, Fatwa; Jankovic‐Karasoulos, Tanja; Roberts, Claire T.; Helbig, Karla J.; Beard, Michael R.

doi:10.1038/s41598-017-04138-1

Cited by 100 publications

(111 citation statements)

References 55 publications

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“…TLR7 is expressed in monocytes, MDMs and plasmacytoid DCs and in B cells (Hornung, Rothenfusser et al 2002, Gantier, Tong et al 2008) while TLR8 is expressed in monocytes, MDMs and myeloid DCs (Hornung, Rothenfusser et al 2002, Alexopoulou, Desnues et al 2012). Analysis of a panel of mutated viperin proteins showed that the carboxy-terminus of the protein was required for antiviral activity, consistent with the findings of Van der Hoek et al who showed that viperin restricts ZIKV replication in Huh7 cells and that virus replication is enhanced in viperin knockout mouse embryonic fibroblasts (Van der Hoek, Eyre et al 2017). …”

Section: Discussionsupporting

confidence: 83%

“…To test the ability of CHME3 cells to support ZIKV replication, we infected them and after 24h quantified intracellular viral RNA and compared the results to blood-derived monocytes and MDMs infected in parallel (Foo, Chen et al 2017, Van der Hoek, Eyre et al 2017). CHME3 cells supported robust ZIKV replication, replicating to a level comparable to that in monocytes.…”

Section: Resultsmentioning

confidence: 99%

“…Infection has been linked to several neurological disorders, particularly congenital microcephaly (Brasil and Nielsen-Saines 2016, Mlakar, Korva et al 2016, White, Wollebo et al 2016). Epidemic strains have the capacity to replicate in diverse cell types of human origin including monocytes, monocytes-derived macrophages (MDMs) and glial cells (Foo, Chen et al 2017, Meertens, Labeau et al 2017, Van der Hoek, Eyre et al 2017). In light of the increased threat posed by the ZIKV epidemic, the development of antiviral therapies to control ZIKV-related disease is a high priority.…”

Section: Introductionmentioning

confidence: 99%

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Toll-like receptor agonist R848 blocks Zika virus replication by inducing the antiviral protein viperin

2018

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Zika virus (ZIKV) is an emerging pathogen linked to neurological disorders for which there is currently no targeted therapy. To identify host innate immune response proteins that restrict ZIKV replication, we treated monocytes and macrophages with toll-like receptor (TLR) agonists. Of those tested, the TLR7/8 agonist R848 (resiquimod) was the most potent. RNA-seq analysis identified several genes strongly induced by R848 in monocytes. Testing of several of these for their ability to restrict ZIKV replication identified viperin, an interferon-induced gene active against several viruses. Transduction of microglial CHME3 cells with a viperin lentiviral expression vector rendered them resistant to ZIKV infection, preventing the synthesis of viral RNA and protein. CRISPR/Cas9 knock-out (KO) of viperin in macrophages relieved the block to infection, demonstrating that viperin is a major innate immune response protein able to block ZIKV replication. TLR agonists may be useful for the prophylactic or therapeutic treatment for ZIKV.

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Section: Discussionsupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Toll-like receptor agonist R848 blocks Zika virus replication by inducing the antiviral protein viperin

2018

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“…Specifically, the IFN-induced transmembrane proteins, IFITM2 and IFITM3, have been shown to restrict infection at early stages of the viral life cycle and provide protection against ZIKV-induced cytopathic effects in HeLa cells [10]. Additionally, viperin, another antiviral ISG, is able to restrict replication in human hepatoma cells; and viperin knockout mouse embryonic fibroblast cells produce higher ZIKV titers than wild-type cells [11]. However, viperin induction was comparatively low in human cells of placental or neural origin upon infection, highlighting the cell-specific nature of ZIKV-induced ISG expression, which is likely influenced by both viral suppression as well as differences in host intrinsic factors [11].…”

Section: Type I Ifn Stimulated Genes Restrict Zikv Infectionmentioning

confidence: 99%

“…Additionally, viperin, another antiviral ISG, is able to restrict replication in human hepatoma cells; and viperin knockout mouse embryonic fibroblast cells produce higher ZIKV titers than wild-type cells [11]. However, viperin induction was comparatively low in human cells of placental or neural origin upon infection, highlighting the cell-specific nature of ZIKV-induced ISG expression, which is likely influenced by both viral suppression as well as differences in host intrinsic factors [11]. Thus, in order to establish an infection, ZIKV must have evolved mechanisms to overcome type I IFN signaling and ISGs.…”

Section: Type I Ifn Stimulated Genes Restrict Zikv Infectionmentioning

confidence: 99%

Zika Virus Infection: Induction, Restriction and Evasion of Host Interferon Responses

2017

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Zika virus (ZIKV) is an arthropod-borne flavivirus that has become a significant global health concern due to its rapid geographic expansion and association with novel neurological pathogenesis [1]. The recent emergence of ZIKV is multifactorial and likely includes the expanded geographical range of Aedes sp. mosquitoes, the immunological naivety of human populations outside of historically endemic regions and global travel of infected individuals [2]. In addition to these epidemiological consequences of globalization, ZIKV has evolved novel mechanisms to induce disease pathogenesis and evade host immune responses [1,2]. Understanding how recently acquired viral polymorphisms influence viral pathogenesis and the host immune response during infection is crucial to further our understanding of ZIKV infection and pathogenesis.ZIKV is a single-stranded, positive-sense RNA virus that encodes a single polyprotein that is catalytically processed by host and viral proteases into three structural proteins (C, prM and E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5). The structural proteins form the virion particle are the primary targets for the host humoral immune response [1,2]. The multifunctional nonstructural proteins have been implicated in polyprotein processing, viral RNA replication, virion assembly, as well as evasion of the innate immune response [1]. Herein, we review recent findings regarding how the interferon (IFN) response restricts ZIKV infection and the ways in which ZIKV is able to overcome IFN signaling to circumvent innate immunity. Type I IFN stimulated genes restrict ZIKV infectionType I IFNs (IFNα/β) are transcriptionally regulated and induced following recognition of pathogen components during infection by various host pattern recognition receptors. Activation of pattern recognition receptors leads to synthesis of type I IFNs that trigger antiviral responses by binding to a common type I IFN receptor. Receptor binding stimulates the JAK kinases, which phosphorylate STAT1 and STAT2, leading to the assembly of the ISGF3 complex, composed of STAT1-STAT2 dimers and IRF9, which translocates to the nucleus and binds to IFN-stimulated response elements in the promoters of interferon stimulated genes (ISGs) to regulate their expression [3,4]. This signaling cascade leads to the transcription of more than 300 ISGs, creating a cellular environment resistant to viral replication. It is well established that type I IFN induction is able to restrict ZIKV infection in cell culture [5][6][7][8] and in mouse models [6,9].Recent investigations have demonstrated that several ISGs are able to restrict ZIKV infection [10]. Specifically, the IFN-induced transmembrane proteins, IFITM2 and IFITM3, have been shown to restrict infection at early stages of the viral life cycle and provide protection against ZIKV-induced cytopathic effects in HeLa cells [10]. Additionally, viperin, another antiviral ISG, is able to restrict replication in human hepatoma cells; and viperin knockout mouse embryo...

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Human viperin catalyzes the modification of GPP and FPP potentially affecting cholesterol synthesis

et al. 2018

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Viperin is a radical SAM enzyme that possesses antiviral properties against a broad range of enveloped viruses. Here, we describe the activity of human viperin with two molecules of the mevalonate pathway, geranyl pyrophosphate, and farnesyl pyrophosphate, involved in cholesterol biosynthesis. We postulate that the radical modification of these two molecules by viperin might lead to defects in cholesterol synthesis, thereby affecting the composition of lipid rafts and subsequent enveloped virus budding.

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Viperin is an important host restriction factor in control of Zika virus infection

Cited by 100 publications

References 55 publications

Toll-like receptor agonist R848 blocks Zika virus replication by inducing the antiviral protein viperin

Toll-like receptor agonist R848 blocks Zika virus replication by inducing the antiviral protein viperin

Zika Virus Infection: Induction, Restriction and Evasion of Host Interferon Responses

Human viperin catalyzes the modification of GPP and FPP potentially affecting cholesterol synthesis

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