Interferon-stimulated genes: roles in viral pathogenesis

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Highlights

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Individual ISGs have measurable phenotypes in vivo.
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ISGs control viral pathogenesis through a variety of mechanisms.
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ISG effects in vivo are often virus-specific, cell-specific, and tissue-specific.

Abstract

Interferon-stimulated genes (ISGs) are critical for controlling virus infections. As new antiviral ISGs continue to be identified and characterized, their roles in viral pathogenesis are also being explored in more detail. Our current understanding of how ISGs impact viral pathogenesis comes largely from studies in knockout mice, with isolated examples from human clinical data. This review outlines recent developments on the contributions of various ISGs to viral disease outcomes in vivo.

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Most cited references 59

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Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays.

S. Der, A. Zhou, B R Williams … (1998)

The pleiotropic activities of interferons (IFNs) are mediated primarily through the transcriptional regulation of many downstream effector genes. The mRNA profiles from IFN-alpha, -beta, or -gamma treatments of the human fibrosarcoma cell line, HT1080, were determined by using oligonucleotide arrays with probe sets corresponding to more than 6,800 human genes. Among these were transcripts for known IFN-stimulated genes (ISGs), the expression of which were consistent with previous studies in which the particular ISG was characterized as responsive to either Type I (alpha, beta) or Type II (gamma) IFNs, or both. Importantly, many novel IFN-stimulated genes were identified that were diverse in their known biological functions. For instance, several novel ISGs were identified that are implicated in apoptosis (including RAP46/Bag-1, phospholipid scramblase, and hypoxia inducible factor-1alpha). Furthermore, several IFN-repressed genes also were identified. These results demonstrate the usefulness of oligonucleotide arrays in monitoring mammalian gene expression on a broad and unprecedented scale. In particular, these findings provide insights into the basic mechanisms of IFN actions and ultimately may contribute to better therapeutic uses for IFNs.

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Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol.

Su-Yang Liu, Roghiyh Aliyari, Kelechi Chikere … (2013)

Interferons (IFN) are essential antiviral cytokines that establish the cellular antiviral state through upregulation of hundreds of interferon-stimulated genes (ISGs), most of which have uncharacterized functions and mechanisms. We identified cholesterol-25-hydroxylase (CH25H) as a broadly antiviral ISG. CH25H converts cholesterol to a soluble antiviral factor, 25-hydroxycholesterol (25HC). 25HC treatment in cultured cells broadly inhibited growth of enveloped viruses including VSV, HSV, HIV, and MHV68 and acutely pathogenic EBOV, RVFV, RSSEV, and Nipah viruses under BSL4 conditions. It suppressed viral growth by blocking membrane fusion between virus and cell. In animal models, Ch25h-deficient mice were more susceptible to MHV68 lytic infection. Moreover, administration of 25HC in humanized mice suppressed HIV replication and reversed T cell depletion. Thus, our studies demonstrate a unique mechanism by which IFN achieves its antiviral state through the production of a natural oxysterol to inhibit viral entry and implicate membrane-modifying oxysterols as potential antiviral therapeutics. Copyright © 2013 Elsevier Inc. All rights reserved.

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Systematic identification of type I and type II interferon-induced antiviral factors.

Su-Yang Liu, David Sanchez, Roghiyh Aliyari … (2012)

Type I and type II interferons (IFNs) are cytokines that establish the cellular antiviral state through the induction of IFN-stimulated genes (ISGs). 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. Based on gene expression studies, we systematically identified antiviral ISGs by performing blinded, functional screens on 288 type I and type II ISGs. We assessed and validated the antiviral activity of these ISGs against an RNA virus, vesicular stomatitis virus (VSV), and a DNA virus, murine gammaherpes virus (MHV-68). Overall, we identified 34 ISGs that elicited an antiviral effect on the replication of either one or both viruses. Fourteen ISGs have uncharacterized antiviral functions. We further defined ISGs that affect critical life-cycle processes in expression of VSV protein and MHV-68 immediate-early genes. Two previously undescribed antiviral ISGs, TAP1 and BMP2, were further validated. TAP1-deficient fibroblasts were more susceptible to VSV infection but less so to MHV-68 infection. On the other hand, exogenous BMP2 inhibits MHV-68 lytic growth but did not affect VSV growth. These results delineate common and distinct sets of type I and type II IFN-induced genes as well as identify unique ISGs that have either broad or specific antiviral effects on these viruses.

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Author and article information

Contributors

John W Schoggins

Journal

Journal ID (nlm-ta): Curr Opin Virol

Journal ID (iso-abbrev): Curr Opin Virol

Title: Current Opinion in Virology

Publisher: Elsevier

ISSN (Print): 1879-6257

ISSN (Electronic): 1879-6265

Publication date PMC-release: 5 April 2014

Publication date (Print): June 2014

Publication date (Electronic): 5 April 2014

Volume: 6

Pages: 40-46

Affiliations

[0005]Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States

Article

Publisher ID: S1879-6257(14)00066-2

DOI: 10.1016/j.coviro.2014.03.006

PMC ID: 4077717

PubMed ID: 24713352

SO-VID: f424a2e6-e5f4-4a0d-af93-277317912247

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Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

Interferon-stimulated genes: roles in viral pathogenesis

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Most cited references 59

Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays.

Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol.

Systematic identification of type I and type II interferon-induced antiviral factors.

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