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Trevor R Sweeney - One of the best experts on this subject based on the ideXlab platform.
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Mouse IFIT1b is a cap1-RNA-binding protein that inhibits mouse coronavirus translation and is regulated by complexing with IFIT1c.
The Journal of biological chemistry, 2020Co-Authors: Harriet V Mears, Trevor R SweeneyAbstract:Knock-out mouse models have been extensively used to study the antiviral activity of interferon-induced protein with tetratricopeptide repeats (IFIT). Human IFIT1 binds to cap0 (m7GpppN) RNA, which lacks methylation on the first and second cap-proximal nucleotides (cap1, m7GpppNm, and cap2, m7GpppNmNm, respectively). These modifications are signatures of 'self' in higher eukaryotes, while unmodified cap0-RNA is recognised as foreign and, therefore, potentially harmful to the host cell. IFIT1 inhibits translation at the initiation stage by competing with the cap-binding initiation factor complex, eIF4F, restricting infection by certain viruses that possess 'non-self' cap0-mRNAs. However, in mice and other rodents the IFIT1 orthologue has been lost and the closely-related IFIT1b has been duplicated twice, yielding three paralogues: IFIT1, IFIT1b and IFIT1c. While murine IFIT1 is similar to human IFIT1 in its cap0-RNA binding selectivity, the roles of IFIT1b and IFIT1c are unknown. Here, we found that IFIT1b preferentially binds to cap1-RNA, while binding is much weaker to cap0- and cap2-RNA. In murine cells, we show that IFIT1b can modulate host translation and restrict wildtype mouse coronavirus infection. We found that IFIT1c acts as a stimulatory cofactor for both IFIT1 and IFIT1b, promoting their translation inhibition. In this way, IFIT1c acts in an analogous fashion to human IFIT3, which is a cofactor to human IFIT1. This work clarifies similarities and differences between the human and murine IFIT families, to facilitate better design and interpretation of mouse models of human infection, and sheds light on the evolutionary plasticity of the IFIT family.
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IFIT1 regulates norovirus infection and enhances the interferon response in murine macrophage like cells
Wellcome open research, 2019Co-Authors: Harriet V Mears, Edward Emmott, Ian Goodfellow, Yasmin Chaudhry, Myra Hosmillo, Trevor R SweeneyAbstract:Background: Norovirus, also known as the winter vomiting bug, is the predominant cause of non-bacterial gastroenteritis worldwide. Disease control is predicated on a robust innate immune response during the early stages of infection. Double-stranded RNA intermediates generated during viral genome replication are recognised by host innate immune sensors in the cytoplasm, activating the strongly antiviral interferon gene programme. Ifit proteins (interferon induced proteins with tetratricopeptide repeats), which are highly expressed during the interferon response, have been shown to directly inhibit viral protein synthesis as well as regulate innate immune signalling pathways. IFIT1 is well-characterised to inhibit viral translation by sequestration of eukaryotic initiation factors or by directly binding to the 5' terminus of foreign RNA, particularly those with non-self cap structures. However, noroviruses have a viral protein, VPg, covalently linked to the 5' end of the genomic RNA, which acts as a cap substitute to recruit the translation initiation machinery. Methods: IFIT1 knockout RAW264.7 murine macrophage-like cells were generated using CRISPR-Cas9 gene editing. These cells were analysed for their ability to support murine norovirus infection, determined by virus yield, and respond to different immune stimuli, assayed by quantitative PCR. The effect of Ifit proteins on norovirus translation was also tested in vitro . Results: Here, we show that VPg-dependent translation is completely refractory to IFIT1-mediated translation inhibition in vitro and IFIT1 cannot bind the 5' end of VPg-linked RNA. Nevertheless, knockout of IFIT1 promoted viral replication in murine norovirus infected cells. We then demonstrate that IFIT1 promoted interferon-beta expression following transfection of synthetic double-stranded RNA but had little effect on toll-like receptor 3 and 4 signalling. Conclusions: IFIT1 is an antiviral factor during norovirus infection but cannot directly inhibit viral translation. Instead, IFIT1 stimulates the antiviral state following cytoplasmic RNA sensing, contributing to restriction of norovirus replication.
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IFIT1 regulates norovirus infection and enhances the interferon response in murine macrophage like cells
bioRxiv, 2019Co-Authors: Harriet V Mears, Edward Emmott, Ian Goodfellow, Yasmin Chaudhry, Myra Hosmillo, Trevor R SweeneyAbstract:Background: Norovirus, also known as the winter vomiting bug, is the predominant cause of non-bacterial gastroenteritis worldwide. Disease control is predicated on a robust innate immune response during the early stages of infection. Double-stranded RNA intermediates generated during viral genome replication are recognised by host innate immune sensors in the cytoplasm, activating the strongly antiviral interferon gene programme. Ifit proteins, which are highly expressed during the interferon response, have been shown to directly inhibit viral protein synthesis as well as regulate innate immune signalling pathways. IFIT1 is well-characterised to inhibit viral translation by sequestration of eukaryotic initiation factors or by directly binding to the 59 terminus of foreign RNA, particularly those with non-self cap structures. However, noroviruses have a viral protein, VPg, covalently linked to the 59 end of the genomic RNA, which acts as a cap substitute to recruit the translation initiation machinery. Methods: IFIT1 knockout RAW264.7 murine macrophage-like cells were generated using CRISPR-Cas9 gene editing. These cells were analysed for their ability to support murine norovirus infection, determined by virus yield, and respond to different immune stimuli, assayed by quantitative PCR. The effect of Ifit proteins on norovirus translation was also tested in vitro. Results: Here, we show that VPg-dependent translation is completely refractory IFIT1-mediated translation inhibition in vitro and IFIT1 cannot bind the 59 end of VPg-linked RNA. Nevertheless, knockout of IFIT1 promoted viral replication in murine norovirus infected cells. We then demonstrate that IFIT1 promoted interferon-beta expression following transfection of synthetic double-stranded RNA, but had little effect on toll-like receptor 3 and 4 signalling. Conclusions: IFIT1 is an antiviral factor during norovirus infection but cannot directly inhibit viral translation. Instead, IFIT1 stimulates the antiviral state following cytoplasmic RNA sensing, contributing to restriction of norovirus replication.
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Study of the regulation of human IFIT1 stability
Access Microbiology, 2019Co-Authors: Xin Yun Leong, Trevor R SweeneyAbstract:Interferon-induced proteins with tetratricopeptide repeats (IFITs) are produced in both interferon-dependent or interferon-independent manners after pathogen-associated molecular pattern recognition. Four IFITs (IFIT1, IFIT2, IFIT3 and IFIT5) have been characterized in humans. They are cytoplasmic proteins with repetitive tetratricopeptide repeats, protein motifs well characterized to mediate protein-protein interactions. IFITs play several functions in cells and their antiviral roles are well established. IFIT1 principally binds non-self cap0 mRNAs and inhibit their translation. On its own, IFIT1 overexpresses poorly in cells. Co-expression with IFIT3 enhances IFIT1 protein levels. Likewise, downregulation of endogenous IFIT3 decreases the expression of IFIT1 at the protein level. The stabilization is dependent on the interaction of the C terminus of IFIT3 with IFIT1 via a specific motif in both proteins, disruption of which greatly reduced IFIT1 stability. It is currently unclear why efficient IFIT1 expression is regulated by its interaction with IFIT3 in this manner. To address this, we have begun to investigate the process of IFIT1 degradation. We have used a range of inhibitors to disrupt specific cellular protein degradation pathways. Surprisingly, inhibition of proteasome and lysosome pathways showed protection of IFIT1 from active degradation, suggesting the protein may be degraded via various routes. We will discuss our current efforts to generate stabilized IFIT1 mutants using random and insertional mutagenesis to identify motifs that may contribute to IFIT1 turnover. These findings will contribute to a deeper understanding of IFITs role during the immune response and may identify methods by which their function can be manipulated.
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Better together: the role of IFIT protein–protein interactions in the antiviral response
The Journal of general virology, 2018Co-Authors: Harriet V Mears, Trevor R SweeneyAbstract:The interferon-induced proteins with tetratricopeptide repeats (IFITs) are a family of antiviral proteins conserved throughout all vertebrates. IFIT1 binds tightly to non-self RNA, particularly capped transcripts lacking methylation on the first cap-proximal nucleotide, and inhibits their translation by out-competing the cellular translation initiation apparatus. This exerts immense selection pressure on cytoplasmic RNA viruses to maintain mechanisms that protect their messenger RNA from IFIT1 recognition. However, it is becoming increasingly clear that protein–protein interactions are necessary for optimal IFIT function. Recently, IFIT1, IFIT2 and IFIT3 have been shown to form a functional complex in which IFIT3 serves as a central scaffold to regulate and/or enhance the antiviral functions of the other two components. Moreover, IFITs interact with other cellular proteins to expand their contribution to regulation of the host antiviral response by modulating innate immune signalling and apoptosis. Here, we summarize recent advances in our understanding of the IFIT complex and review how this impacts on the greater role of IFIT proteins in the innate antiviral response.
Abraham L Brass - One of the best experts on this subject based on the ideXlab platform.
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The IFITMs Inhibit Zika Virus Replication
Cell Reports, 2016Co-Authors: George Savidis, Jill M. Perreira, Paul Meraner, Zhiru Guo, Sharone Green, Jocelyn M. Portmann, Abraham L BrassAbstract:Summary Zika virus has emerged as a severe health threat with a rapidly expanding range. The IFITM family of restriction factors inhibits the replication of a broad range of viruses, including the closely related flaviruses West Nile virus and dengue virus. Here, we show that IFITM1 and IFITM3 inhibit Zika virus infection early in the viral life cycle. Moreover, IFITM3 can prevent Zika-virus-induced cell death. These results suggest that strategies to boost the actions and/or levels of the IFITMs might be useful for inhibiting a broad range of emerging viruses.
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distinct patterns of ifitm mediated restriction of filoviruses sars coronavirus and influenza a virus
PLOS Pathogens, 2011Co-Authors: Ichueh Huang, Jessica L Weyer, Sheli R Radoshitzky, Jessica J Chiang, Abraham L Brass, Xiaoli Chi, Charles C. Bailey, Michelle M Becker, Asim A Ahmed, Lian DongAbstract:Interferon-inducible transmembrane proteins 1, 2, and 3 (IFITM1, 2, and 3) are recently identified viral restriction factors that inhibit infection mediated by the influenza A virus (IAV) hemagglutinin (HA) protein. Here we show that IFITM proteins restricted infection mediated by the entry glycoproteins (GP1,2) of Marburg and Ebola filoviruses (MARV, EBOV). Consistent with these observations, interferon-b specifically restricted filovirus and IAV entry processes. IFITM proteins also inhibited replication of infectious MARV and EBOV. We observed distinct patterns of IFITM-mediated restriction: compared with IAV, the entry processes of MARV and EBOV were less restricted by IFITM3, but more restricted by IFITM1. Moreover, murine Ifitm5 and 6 did not restrict IAV, but efficiently inhibited filovirus entry. We further demonstrate that replication of infectious SARS coronavirus (SARS-CoV) and entry mediated by the SARS-CoV spike (S) protein are restricted by IFITM proteins. The profile of IFITM-mediated restriction of SARS-CoV was more similar to that of filoviruses than to IAV. Trypsin treatment of receptor-associated SARS-CoV pseudovirions, which bypasses their dependence on lysosomal cathepsin L, also bypassed IFITM-mediated restriction. However, IFITM proteins did not reduce cellular cathepsin activity or limit access of virions to acidic intracellular compartments. Our data indicate that IFITM-mediated restriction is localized to a late stage in the endocytic pathway. They further show that IFITM proteins differentially restrict the entry of a broad range of enveloped viruses, and modulate cellular tropism independently of viral receptor expression.
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the ifitm proteins mediate cellular resistance to influenza a h1n1 virus west nile virus and dengue virus
Cell, 2009Co-Authors: Abraham L Brass, Ichueh Huang, Yair Benita, Sinu P John, Manoj N Krishnan, Eric M Feeley, Bethany J Ryan, Jessica L WeyerAbstract:Influenza viruses exploit host cell machinery to replicate, resulting in epidemics of respiratory illness. In turn, the host expresses antiviral restriction factors to defend against infection. To find host cell modifiers of influenza A H1N1 viral infection, we used a functional genomic screen and identified over 120 influenza A virus-dependency factors with roles in endosomal acidification, vesicular trafficking, mitochondrial metabolism, and RNA splicing. We discovered that the interferon-inducible transmembrane proteins IFITM1, 2, and 3 restrict an early step in influenza A viral replication. The IFITM proteins confer basal resistance to influenza A virus but are also inducible by interferons type I and II and are critical for interferon's virustatic actions. Further characterization revealed that the IFITM proteins inhibit the early replication of flaviviruses, including dengue virus and West Nile virus. Collectively this work identifies a family of antiviral restriction factors that mediate cellular innate immunity to at least three major human pathogens.
Sineewanlaya Wichit - One of the best experts on this subject based on the ideXlab platform.
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SAMHD1 Enhances Chikungunya and Zika Virus Replication in Human Skin Fibroblasts
Proceedings, 2020Co-Authors: Sineewanlaya WichitAbstract:Chikungunya virus (CHIKV) and Zika virus (ZIKV) are emerging arboviruses that pose a worldwide threat to human health. Currently, neither vaccine nor antiviral treatment to control their infections is available. As the skin is a major viral entry site for arboviruses in the human host, we determined the global proteomic profile of CHIKV and ZIKV infections in human skin fibroblasts using stable isotope labelling by amino acids in cell culture (SILAC)-based mass spectrometry analysis. We show that the expressions of the interferon-stimulated proteins MX1, IFIT1, IFIT3 and ISG15, as well as expressions of defense response proteins DDX58, STAT1, OAS3, EIF2AK2, and SAMHD1 were significantly upregulated in these cells upon infection with either virus. Exogenous expression of IFITs proteins markedly inhibited CHIKV and ZIKV replication which, accordingly, was restored following the abrogation of IFIT1 or IFIT3. Overexpression of SAMHD1 in cutaneous cells or pretreatment of cells with the virus-like particles containing SAMHD1 restriction factor Vpx resulted in a strong increase or inhibition, respectively, in both CHIKV and ZIKV replication. Moreover, silencing of SAMHD1 by specific SAMHD1-siRNA resulted in a marked decrease in viral RNA levels. Together, these results suggest that IFITs are involved in the restriction of replication of CHIKV and ZIKV and provide, as yet unreported, evidence for a proviral role of SAMHD1 in arbovirus infection of human skin cells.
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SAMHD1 Enhances Chikungunya and Zika Virus Replication in Human Skin Fibroblasts.
International Journal of Molecular Sciences, 2019Co-Authors: Sineewanlaya Wichit, Andreas Zanzoni, Rodolphe Hamel, Fode Diop, Alexandra Cribier, Loïc Talignani, Abibatou Diack, Pauline Ferraris, Florian Liegeois, Serge UrbachAbstract:Chikungunya virus (CHIKV) and Zika virus (ZIKV) are emerging arboviruses that pose a worldwide threat to human health. Currently, neither vaccine nor antiviral treatment to control their infections is available. As the skin is a major viral entry site for arboviruses in the human host, we determined the global proteomic profile of CHIKV and ZIKV infections in human skin fibroblasts using Stable Isotope Labelling by Amino acids in Cell culture (SILAC)-based mass-spectrometry analysis. We show that the expression of the interferon-stimulated proteins MX1, IFIT1, IFIT3 and ISG15, as well as expression of defense response proteins DDX58, STAT1, OAS3, EIF2AK2 and SAMHD1 was significantly up-regulated in these cells upon infection with either virus. Exogenous expression of IFITs proteins markedly inhibited CHIKV and ZIKV replication which, accordingly, was restored following the abrogation of IFIT1 or IFIT3. Overexpression of SAMHD1 in cutaneous cells, or pretreatment of cells with the virus-like particles containing SAMHD1 restriction factor Vpx, resulted in a strong increase or inhibition, respectively, of both CHIKV and ZIKV replication. Moreover, silencing of SAMHD1 by specific SAMHD1-siRNA resulted in a marked decrease of viral RNA levels. Together, these results suggest that IFITs are involved in the restriction of replication of CHIKV and ZIKV and provide, as yet unreported, evidence for a proviral role of SAMHD1 in arbovirus infection of human skin cells.
Andreas Pichlmair - One of the best experts on this subject based on the ideXlab platform.
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structural basis for viral 5 ppp rna recognition by human ifit proteins
Nature, 2013Co-Authors: Yazan M. Abbas, Andreas Pichlmair, Maria W Gorna, Giulio Supertifurga, Bhushan NagarAbstract:Interferon-induced proteins with tetratricopeptide repeats (IFITs) are innate immune effector molecules that are thought to confer antiviral defence through disruption of protein-protein interactions in the host translation-initiation machinery. However, it was recently discovered that IFITs can directly recognize viral RNA bearing a 5'-triphosphate group (PPP-RNA), which is a molecular signature that distinguishes it from host RNA. Here we report crystal structures of human IFIT5, its complex with PPP-RNAs, and an amino-terminal fragment of IFIT1. The structures reveal a new helical domain that houses a positively charged cavity designed to specifically engage only single-stranded PPP-RNA, thus distinguishing it from the canonical cytosolic sensor of double-stranded viral PPP-RNA, retinoic acid-inducible gene I (RIG-I, also known as DDX58). Mutational analysis, proteolysis and gel-shift assays reveal that PPP-RNA is bound in a non-sequence-specific manner and requires a 5'-overhang of approximately three nucleotides. Abrogation of PPP-RNA binding in IFIT1 and IFIT5 was found to cause a defect in the antiviral response by human embryonic kidney cells. These results demonstrate the mechanism by which IFIT proteins selectively recognize viral RNA, and lend insight into their downstream effector function.
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IFIT1 is an antiviral protein that recognizes 5 triphosphate rna
Nature Immunology, 2011Co-Authors: Andreas Pichlmair, Maria W Gorna, Caroline Lassnig, Tilmann Bürckstümmer, Thomas R Burkard, Adrijana Stefanovic, Carol-ann Eberle, Christoph Baumann, Sigurd Krieger, Keiryn L. BennettAbstract:Antiviral innate immunity relies on the recognition of microbial structures. One such structure is viral RNA that carries a triphosphate group on its 5' terminus (PPP-RNA). By an affinity proteomics approach with PPP-RNA as the 'bait', we found that the antiviral protein IFIT1 (interferon-induced protein with tetratricopeptide repeats 1) mediated binding of a larger protein complex containing other IFIT family members. IFIT1 bound PPP-RNA with nanomolar affinity and required the arginine at position 187 in a highly charged carboxy-terminal groove of the protein. In the absence of IFIT1, the growth and pathogenicity of viruses containing PPP-RNA was much greater. In contrast, IFIT proteins were dispensable for the clearance of pathogens that did not generate PPP-RNA. On the basis of this specificity and the great abundance of IFIT proteins after infection, we propose that the IFIT complex antagonizes viruses by sequestering specific viral nucleic acids.
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IFIT1 is an antiviral protein that recognises 5'-triphosphate RNA
Nature Immunology, 2011Co-Authors: Giulio Superti-furga, Andreas Pichlmair, Caroline Lassnig, Christoph L Baumann, Tilmann Bürckstümmer, Thomas R Burkard, Adrijana Stefanovic, Keiryn Bennet, Jacques Colinge, Thomas RülickeAbstract:Antiviral innate immunity relies on recognition of microbial structures. One such structure is viral RNA that carries a triphosphate group on its 5'terminus (PPP-RNA). In an affinity proteomics approach with PPP-RNA as bait we identified interferon induced protein with tetratricopeptide repeats 1 (IFIT1) to mediate binding of a larger protein complex containing other IFIT proteins. IFIT1 bound PPP-RNA with nanomolar affinity and required R187 in a highly charged groove. In the absence of IFIT1 growth and pathogenicity of PPP-RNA viruses were severely increased. In contrast, IFITs were dispensable for clearance of pathogens not generating PPP-RNA. Based on this specificity and the high abundance of IFITs we propose that the IFIT complex antagonises viruses by sequestering specific viral nucleic acids.
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IFIT1 is an antiviral protein that recognizes 5′-triphosphate RNA
Nature immunology, 2011Co-Authors: Andreas Pichlmair, Maria W Gorna, Caroline Lassnig, Tilmann Bürckstümmer, Thomas R Burkard, Adrijana Stefanovic, Carol-ann Eberle, Christoph Baumann, Sigurd Krieger, Keiryn L. BennettAbstract:Antiviral innate immunity relies on the recognition of microbial structures. One such structure is viral RNA that carries a triphosphate group on its 5' terminus (PPP-RNA). By an affinity proteomics approach with PPP-RNA as the 'bait', we found that the antiviral protein IFIT1 (interferon-induced protein with tetratricopeptide repeats 1) mediated binding of a larger protein complex containing other IFIT family members. IFIT1 bound PPP-RNA with nanomolar affinity and required the arginine at position 187 in a highly charged carboxy-terminal groove of the protein. In the absence of IFIT1, the growth and pathogenicity of viruses containing PPP-RNA was much greater. In contrast, IFIT proteins were dispensable for the clearance of pathogens that did not generate PPP-RNA. On the basis of this specificity and the great abundance of IFIT proteins after infection, we propose that the IFIT complex antagonizes viruses by sequestering specific viral nucleic acids.
Michael S. Diamond - One of the best experts on this subject based on the ideXlab platform.
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human ifit3 modulates IFIT1 rna binding specificity and protein stability
Immunity, 2018Co-Authors: Britney Johnson, Laura A Vanblargan, James P White, Chao Shan, Pei Yong Shi, Rong Zhang, Jagat Adhikari, Michael L Gross, Daisy W Leung, Michael S. DiamondAbstract:Although interferon-induced proteins with tetratricopeptide repeats (IFIT proteins) inhibit infection of many viruses by recognizing their RNA, the regulatory mechanisms involved remain unclear. Here we report a crystal structure of cap 0 (m7GpppN) RNA bound to human IFIT1 in complex with the C-terminal domain of human IFIT3. Structural, biochemical, and genetic studies suggest that IFIT3 binding to IFIT1 has dual regulatory functions: (1) extending the half-life of IFIT1 and thereby increasing its steady-state amounts in cells; and (2) allosterically regulating the IFIT1 RNA-binding channel, thereby enhancing the specificity of recognition for cap 0 but not cap 1 (m7GpppNm) or 5'-ppp RNA. Mouse Ifit3 lacks this key C-terminal domain and does not bind mouse IFIT1. The IFIT3 interaction with IFIT1 is important for restricting infection of viruses lacking 2'-O methylation in their RNA cap structures. Our experiments establish differences in the regulation of IFIT1 orthologs and define targets for modulation of human IFIT protein activity.
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The broad-spectrum antiviral functions of IFIT and IFITM proteins
Nature Reviews Immunology, 2013Co-Authors: Michael S. Diamond, Michael FarzanAbstract:Over the past few years, several groups have identified new genes that are transcriptionally induced downstream of type I interferon (IFN) signalling and that inhibit infection by individual or multiple families of viruses. Among these IFN-stimulated genes with antiviral activity are two genetically and functionally distinct families — the IFN-induced protein with tetratricopeptide repeats (IFIT) family and the IFN-induced transmembrane protein (IFITM) family. This Review focuses on recent advances in identifying the unique mechanisms of action of IFIT and IFITM proteins, which explain their broad-spectrum activity against the replication, spread and pathogenesis of a range of human viruses. Recent interest in identifying interferon-stimulated genes that have activity against a wide range of viruses has advanced our understanding of the IFIT and IFITM families and shown the many mechanisms by which host factors can restrict viral replication. IFN-induced protein with tetratricopeptide repeats (IFIT) proteins — which are induced after type I interferon (IFN)- or IFN-regulatory factor 3 (IRF3)-dependent signalling — contribute to antiviral defence against some viruses by binding to components of the eukaryotic initiation factor 3 (eIF3) translation initiation complex and inhibiting protein translation. Mutant flaviviruses, poxviruses and coronaviruses lacking 2′- O methyltransferase enzymes are attenuated in wild-type primary cells and mice but pathogenic in the absence of IFIT1 expression. Thus, IFIT proteins restrict viruses lacking 2′- O methylation of the 5′ RNA cap. IFIT proteins form a multiprotein complex to bind viral RNA displaying a 5′-ppp motif. By sequestering viral RNA containing 5′-ppp, IFIT proteins function as both a pathogen sensor and an effector molecule. IFN-induced transmembrane protein (IFITM) proteins constitute a family of small IFN-inducible proteins. Unlike IFIT proteins, IFITM proteins have two transmembrane domains and block the replication of enveloped viruses, including influenza A virus, dengue virus, Ebola virus and SARS coronavirus, at a step before these viruses enter the cytosol. IFITM proteins seem to be specialized in their activity. IFITM3 makes the primary contribution to the control of influenza A virus in mice and probably humans, whereas other human and mouse IFITM proteins more efficiently restrict infection by Ebola virus and SARS coronavirus. The mechanisms by which IFITM proteins prevent the entry of enveloped viruses remain unclear, but they probably involve alterations in the properties or the trafficking of intracellular compartments where these viruses traverse cellular membranes.
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Interferon-Induced Ifit2/ISG54 Protects Mice from Lethal VSV Neuropathogenesis
PLoS pathogens, 2012Co-Authors: Volker Fensterl, Jaime L. Wetzel, Srividya Ramachandran, Tomoaki Ogino, Stephen A. Stohlman, Cornelia C. Bergmann, Michael S. Diamond, Herbert W. Virgin, Ganes C. SenAbstract:Interferon protects mice from vesicular stomatitis virus (VSV) infection and pathogenesis; however, it is not known which of the numerous interferon-stimulated genes (ISG) mediate the antiviral effect. A prominent family of ISGs is the interferon-induced with tetratricopeptide repeats (Ifit) genes comprising three members in mice, IFIT1/ISG56, Ifit2/ISG54 and Ifit3/ISG49. Intranasal infection with a low dose of VSV is not lethal to wild-type mice and all three Ifit genes are induced in the central nervous system of the infected mice. We tested their potential contributions to the observed protection of wild-type mice from VSV pathogenesis, by taking advantage of the newly generated knockout mice lacking either Ifit2 or IFIT1. We observed that in Ifit2 knockout (Ifit2−/−) mice, intranasal VSV infection was uniformly lethal and death was preceded by neurological signs, such as ataxia and hind limb paralysis. In contrast, wild-type and IFIT1−/− mice were highly protected and survived without developing such disease. However, when VSV was injected intracranially, virus replication and survival were not significantly different between wild-type and Ifit2−/− mice. When administered intranasally, VSV entered the central nervous system through the olfactory bulbs, where it replicated equivalently in wild-type and Ifit2−/− mice and induced interferon-β. However, as the infection spread to other regions of the brain, VSV titers rose several hundred folds higher in Ifit2−/− mice as compared to wild-type mice. This was not caused by a broadened cell tropism in the brains of Ifit2−/− mice, where VSV still replicated selectively in neurons. Surprisingly, this advantage for VSV replication in the brains of Ifit2−/− mice was not observed in other organs, such as lung and liver. Pathogenesis by another neurotropic RNA virus, encephalomyocarditis virus, was not enhanced in the brains of Ifit2−/− mice. Our study provides a clear demonstration of tissue-, virus- and ISG-specific antiviral action of interferon.
