Both type i and type ii interferon significantly induce expression of the mx, p47, and p65 families of gtpases, which hydrolyze gtp and are wellknown to confer resistance against a wide range of pathogens. Ifnstimulated genes isgs associated with an ifninducible antiviral response, revealed that the expression levels for these isgs were not. Systematic identification of type i and type ii interferoninduced. In addition to antiviral, antibacterial and antiparasitic hostdefense functions they are now also recognized as crucial regulators of cell proliferation, differentiation, survival and death as well as activators of specialized cell functions particularly in the. Ifn inducible transmembrane ifitm proteins have been identified as intrinsic antiviral effectors, which block the entry of a broad spectrum of enveloped rna viruses by interrupting virusendosomal fusion. Irg1 and inducible nitric oxide synthase act redundantly with. West nile virus wnv is a member of japanese encephalitis serogroup of flavivirus genus, family flaviviridae, which is distributed globally across temperate and tropical climates. Choose from 300 different sets of interferon flashcards on quizlet. We sought to understand the basis of the antiviral activity induced by type i and ii ifns in relation to the functions of their isgs. Many of these substrates are important in the ifn response, including the signalling components jak1 and stat1, prrs such as rigi retinoicacid inducible gene i, and the antiviral effector proteins mxa, pkr and rnasel 24. Induction of type i interferons ifns, a wellknown subset of cytokines with antiviral activity, is triggered by a selection of cellular pattern recognition receptors, including tlrs tolllike receptors, rigi retinoic acidinducible gene i, and mda5 melanoma differentiationassociated protein 5. Clinical studies suggest that the occurrence and persistence of chronic hev infection are related to the immunological status of patients.
Release of interferon after viral recognition signals to cells to induce the expression of a set of interferon stimulated genes isgs that activate antiviral processes including amplification of interferon signaling, production of cytokines that activate adaptive immunity, and many factors that directly inhibit viruses. Unlike ubiquitylation, isgylation does not drive protein degradation regulated by k48linked. Isgs are the effectors of the initial host antiviral response and are engaged in a wide array of functions in the cell. Viral genomic rna encodes for 3 structural, 7 nonstructural proteins and viral noncoding rna. Macmicking jd 2012 interferoninducible effector mechanisms in cellautonomous immunity. Viperin virus inhibitory protein, endoplasmic reticulumassociated, interferoninducible is an ifninducible protein. However, the ifit family in the dog genome is split between two chromosomes.
Neurotropic flaviviruses such as tickborne encephalitis virus tbev, japanese encephalitis virus jev, west nile virus wnv, and zika virus zikv are causative agents of severe brainrelated diseases including meningitis, encephalitis, and microcephaly. Interferons are a group of antiviral cytokines acting as the first line of defense in the antiviral immunity. They have antiviral activity that is involved mainly in innate immune response. Type i interferon receptorindependent and dependent host. Insight into the effector functions of isgencoded proteins, however, has been limited primarily. In the present study, we investigate suppressor of cytokine. It was discovered, a while ago in 1957 by isaacs and lindenmann, who found that interferon was a cellular factor with antiviral activity, secreted when they treat sickle cells with partially heatinactivated influenza viruses. Journal of neuroinflammation, issn 17422094, eissn 17422094, vol. Thus, the cellular effectors that limit the spread of viral infection are the products of isgs. In europe, hev causes a porcine zoonosis and is an emerging causative agent of autochthonous acute hepatitis, which is caused by hev genotype 3. Department of animal sciences, washington state university, pullman, wa 991646351, usa 2.
The first isgs were discovered more than 25 years ago 7, 8, and the past decade has seen genomescale cataloging of these molecules. However, among the more than 300 isgs induced by ifn signaling, the exact mechanism. Viperin virus inhibitory protein, endoplasmic reticulumassociated, interferon inducible is an ifn inducible protein that has recently received increasing attention. When they moved the supernatum from these chicken cells, in to new chicken cells, they found that these new chicken. The interferon response protects cells from invading viral pathogens by transcriptionally inducing the expression of interferon stimulated genes isgs, some. Identification of interferonstimulated genes with antiretroviral activity. Jan 08, 2015 sadler aj, williams br 2008 interferon. Frontiers the host restriction factor interferoninducible. Interferons ifns establish dynamic host defense mechanisms by inducing various ifnstimulated genes that encodes many antiviral innate immune effectors. The mechanisms of selfregulation and control of this pathway allow precise and environmentdependent response of the cells in different conditions. Type i interferon ifni play a critical role in the innate immune response against viral infections. Crossspecies antiviral activity of goose interferons against. Pmc free article saitoh t, satoh t, yamamoto n, uematsu s, takeuchi o, kawai t, akira s. All type i ifns bind to a specific cell surface receptor complex known as the ifn.
The type i ifn response limits tbev replication in astrocytes. Irg1 and inducible nitric oxide synthase act redundantly. Since the discovery of interferons ifns, considerable progress has been made in describing the nature of the cytokines themselves, the signalling components. Systematic identification of antiinterferon function on. Although type i interferons ifnskey effectors of antiviral innate immunity are known to be induced via different pattern recognition receptors prrs, the cellular source and the relative contribution. Interferon induced ifit family genes in host antiviral defense. Influenza virus nonstructural protein 1 ns1 disrupts. Schoggins jw, wilson sj, panis m, murphy my, jones ct, et al. Hepatitis e virus hev is a new causative agent of chronic hepatitis in solid organ transplant recipients. Interferon regulation of the innate response to bacteria. The transcription factor foxk participates with nup98 to. Apr 10, 2011 to identify novel antiviral effectors in the type i interferon ifn system, we developed a cellbased assay to determine the effects of hundreds of isg products on viral replication. The interferons ifns are a family of cytokines identified more than 50 years ago as potent antiviral proteins. Antiviral protein viperin promotes tolllike receptor 7 and tolllike receptor 9mediated type i interferon production in plasmacytoid dendritic cells.
Sadler and williams, 2008, the functions of most ifninducible proteins remain unexplored. To investigate the importance of type i ifns for astrocyte function in neurotropic flavivirus infection, primary astrocytes were isolated from wildtype wt and ifnar. Type i ifns are found in all mammals, and homologous similar molecules have been found. Our lab, named interferon and antiviral restriction, which has been established in january 2015 at the cnrs institute of research on infection of montpellier irim, excpbs, aims at identifying new cellular effectors of the antiviral state using, among other approaches, wholegenome scale crisprcas9 screens and at characterizing the. This results in the activation of transcription factors that initiate antiviral and proinflammatory gene expression.
We have previously shown that local type i interferon response within the central nervous system cns is involved in the protection of. Interferon inducible ribonuclease isg20 inhibits hepatitis b virus replication through directly binding to the epsilon stemloop structure of viral rna. Oct, 2008 respiratory syncytial virus rsv is a major cause of severe lower airway disease in infants and young children, but no safe and effective rsv vaccine is yet available. Randall2 1 department of biochemistry and immunology, st georges hospital medical school, university of london, london sw17 0re, uk 2 biomolecular sciences building, north haugh, university of st andrews, fife. Gene targeting studies have distinguished four main effector pathways of the ifnmediated antiviral response. The ifn system can be dangerous ifn induces the expression of many deleterious gene products most of our cells have ifn receptors ifns have dramatic physiological consequences. The ifit family is clustered on chromosomes 10 in human, 9 in rhesus, 12 in marmoset, 10 in orangutan, 14 in pig, 26 in cattle, 1 in horse, 19 in mouse, 1 in rat, 1 in opossum, 6 in chicken and 12 in zebrafish, but has not been placed on chromosomes in gibbon and frog. Mar 12, 2018 read the original article in full on fresearch. Interferon induced ifit family genes in host antiviral defense xiang zhou 1,2, jennifer j.
Sadler aj, williams br 2008 interferoninducible antiviral effectors. New developments in the induction and antiviral effectors. Cytokines are key regulators that dictate many aspects of innate and adaptive immunity. Depending on cell type, ifn dose, and time of treatment, microarray studies identify 50 isgs, with 200500 genes typical of many cell types 9, 10, 11.
Astrocytes are the most abundant glial cell type in the brain and an important source of type i ifn during various neurotropic viral infections 18, 22, 23. They actively participate in antiviral immunity by inducing molecular mechanisms of viral restriction and by limiting the spread of the infection, but they also orchestrate the initial phases of the adaptive immune response and influence the quality of t cell immunity. Interferoninduced ifit2isg54 protects mice from lethal. Despite advances in understanding the molecular basis of isg restriction, the antiviral mechanisms of many remain unclear. Interferon ifn responses, mediated by a myriad of ifnstimulated genes isgs, are the most profound innate immune responses against viruses. Interferonstimulated genesessential antiviral effectors. Hepatitis e virus hev is a small nonenveloped virus, and its genome is a singlestranded, linear, positivesense rna. Interferons ifns are potent activators of these antiviral factors. Dengue reporter viruses reveal viral dynamics in interferon receptordeficient mice and sensitivity to interferon effectors in vitro. New developments in the induction and antiviral effectors of. In developing countries, hev is a leading cause of waterborne acute hepatitis in adults 2, 3. For example, intracellular replication of the bacterial pathogen legionella pneumophila in macrophages is potently curtailed by ifn however, consistent with prior studies, no individual genetic deficiency that we. Human type i interferons ifns are a large subgroup of interferon proteins that help regulate the activity of the immune system interferons bind to interferon receptors.
Sadler and williams, 2008, the functions of most ifn inducible proteins remain unexplored. Interferonstimulated genes as enhancers of antiviral innate. Type i interferon at the interface of antiviral immunity. Interferoninducible antiviral effectors researchgate. Interferoninducible ribonuclease isg20 inhibits hepatitis b virus replication through directly binding to the epsilon stemloop structure of viral rna. Considerable genetic and functional characterizations of mammalian ifns and their effectors have been made, and our. The interferon response protects cells from invading viral pathogens by transcriptionally inducing the expression of interferonstimulated genes isgs, some. Interferoninducible mx2 is a host restriction factor of. Fast type i interferon response protects astrocytes from. At least 158 putative isg15 target proteins have been identified to date 2426. Factors attributing to this problem are associated with an incomplete understanding of the mechanisms by which rsv modulates the host cell response to infection. Interferoninducible oligoadenylate synthetaselike protein acts as. The interferoninduced exonuclease isg20 exerts antiviral. An emerging class of broad spectrum antiviral effectors, molecular aspects of medicine on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips.
The ifninducible oass are important components of the antiviral activity of ifns and are involved in other cellular. The pegylated types are pegylated interferon alfa2a and pegylated interferon alfa2b. Positive feedback regulation of type i interferon by the. Frontiers avian interferons and their antiviral effectors. Chronic hepatitis e virus infection is specifically. Upon infection, pathogen recognition leads to a rapidly activated gene expression program that induces antimicrobial effectors to clear the invader. Crossspecies antiviral activity of goose interferons. Based on the type of receptor through which they signal, human interferons have been classified into three major types interferon type i.
Brunette rl, young jm, whitley dg, brodsky ie, malik hs, stetson db 2012 extensive evolutionary and functional diversity among mammalian aim2. Recent advances in antiviral interferonstimulated gene biology read the latest article version by john w. Expression of an array of antiviral effectors may be an effective. Interferoninduced ifit2isg54 protects mice from lethal vsv. Interferonbeta ifnbeta activates the immune response through the type i ifn signaling pathway. Welzel tm, morgan tr, bonkovsky hl, naishadham d, pfeiffer rm, et al. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a pdf plugin installed and enabled in your browser. Jan 31, 2017 interferon ifn responses, mediated by a myriad of ifnstimulated genes isgs, are the most profound innate immune responses against viruses. Since the discovery of interferons ifns, considerable progress has been made in describing the nature of the cytokines themselves, the signalling. Interferonstimulated genesinterferoninnate immunityvirus. This is a small enveloped virus with ssrna genome of positive polarity, which is capped, but not polyadenylated. We recently found that nup98 regulates the expression of a subset of rapidly activated antiviral genes to restrict disparate rna virus infections in drosophila by promoting rna polymerase occupancy at the promoters of these antiviral genes.
Type i interferon ifnstimulated genes isgs have critical roles in inhibiting virus replication and dissemination. Interferonstimulated genes and their antiviral effector. Interferon, viruses, antiviral state, interferoninducible genes, ifi200, hin200. Interferoninducible antiviral effectors europe pmc article europe. When used with the antiviral drug ribavirin, pegylated interferon is effective in treatment of hepatitis c. Recent advances in antiviral interferon stimulated gene biology read the latest article version by john w. Avian interferons and their antiviral effectors frontiers. Cumulatively, these ifn effectors establish a multilayered antiviral state to safeguard the host against invading viral pathogens. Induction of type i interferons ifns, a wellknown subset of cytokines with antiviral activity, is triggered by a selection of cellular pattern recognition receptors, including tlrs tolllike receptors, rigi retinoic acid inducible gene i, and mda5 melanoma differentiationassociated protein 5. Ifninducible transmembrane ifitm proteins have been identified as intrinsic antiviral effectors, which block the entry of a broad spectrum of enveloped rna viruses by interrupting virusendosomal fusion. Nih public access, and peter cresswell department of. Many of these substrates are important in the ifn response, including the signalling components jak1 and stat1, prrs such as rigi retinoicacidinducible gene i, and the antiviral effector proteins mxa, pkr and rnasel 24.
Gene targeting studies have distinguished four effector pathways of the ifnmediated antiviral response. Interferon, viruses, antiviral state, interferon inducible genes, ifi200, hin200. The mx proteins inhibits replication of orthomyxoviruses, thogoto virus, bunyaviruses and rhabdoviruses 11,26. Antiviral interferonbeta signaling induced by designed.628 1178 1032 1149 1031 48 1095 1013 1432 850 1626 1353 817 260 1101 79 1629 1631 134 523 1133 357 1452 554 77 1133 1556 363 638 653 819 113 1403 1395 301 328 433 1309