New developments in the induction and antiviral effectors of type I interferon

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Type I interferons (IFNs) are cytokines of the innate immune system that induce antiviral protein expression in response to viral infection. Various proteins and pathways have been shown to recognize nucleic acid ligands especially from RNA viruses. Here, we will review recent developments including transcription of DNA virus genomes into RNA ligands, and the recognition of viruses by TLR2 for interferon induction. The induced IFNs activate many interferon stimulated genes (ISGs) that have direct antiviral effects. Recent studies have identified IFITM proteins as the first ISG to inhibit viral entry processes and revealed mechanistic understanding of known antiviral ISGs such as ISG15 and Viperin.

Introduction

Type I interferon (IFN) is a key innate immune cytokine produced by cells to combat viral infections. Intricate sensory mechanisms detect invading viruses and rapidly trigger interferon production. Recognition of distinctive viral nucleic acids as a pathogen associated molecular patterns (PAMPs) by cellular pattern recognition receptors (PRRs) will lead to IFN induction. While RNA virus recognition is well understood, new pathways are constantly being elucidated and the receptor for DNA viruses is a subject of intense research. The first part of this review will discuss recent advances in understanding how virus infection leads to IFN production.

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. ISGs with direct antiviral functions remain poorly understood, largely because they are virus-specific and can have multiple mechanisms. The second part of this review will cover well-known and novel ISGs focusing on recent developments in understanding their antiviral function.

Section snippets

Old and new paths to IFN induction

The mechanism involved in how cells exposed to viruses or virion components ‘know’ to release IFN has not been well understood until recently. The discovery of the Toll like receptors (TLRs) as receptors for extracellular or endocytosed viral components was a major advance in understanding viral recognition in the IFN process [1]. Likewise, the recent discovery of the RIG-I-like RNA Helicases as RNA virus sensors has elucidated how a cell detects an active intracellular virus infection [2].

New players in recognition of DNA virus infection

A search for the primary DNA virus receptor has fueled much research over the past years. From the discovery of DAI, a protein that seemed critical for DNA induced IFN to the in vivo finding that DAI may be redundant, many groups have searched for the ‘key’ DNA receptor or sought to understand how DNA recognition occurs [5, 6]. A major development is the discovery that the protein STING is necessary for IFN induction by exposure to B-DNA and the DNA virus HSV-1 [7••, 8••]. STING is an

TLR2 as a virus receptor for interferon induction

The endosomal TLRs 3, 7, 8 recognize extracellular viral RNA PAMPs, while TLR9 recognizes CpG DNA and can lead to IFN production upon activation. Other TLRs were thought to primarily be inducers of inflammatory cytokines, none more so than TLR2.

However, in inflammatory monocytes, a small distinct fraction of bone marrow, TLR2 was found to be required for vaccinia virus induced IFN induction [10]. Ablation of this cell type, which is not present in standard bone marrow derived macrophages or

Interferon stimulated genes

Viral recognition induces the release of IFN that signals to surrounding cells creating the ‘antiviral state’ that was described as far back as the original IFN studies. Expression array studies have shown that hundreds of genes are induced by IFN. While some ISGs such as protein kinase R (PKR), 2′5-oligoadenylate synthetase, and Mx GTPases have well described antiviral functions and mechanisms [11, 12, 13], functions of most ISGs are poorly characterized with little or no mechanistic

IFITM3

The interferon induced transmembrane (IFITM) proteins 1, 2, and 3 were identified as the first host factors that restrict viral entry [14••]. Brass showed that overexpression of IFITM 2 and 3 significantly inhibited influenza, VSV, West Nile, and Dengue virus [14••]. Conversely, knockdown of IFITM3 or deletion of the Ifitm locus in murine embryonal fibroblast (MEF) increased susceptibility of the cells to viral infections. IFITM3 inhibited influenza pseudoviruses but not Machupo pseudoviruses,

ISG15

ISG15 is a 17 kDa ubiquitin-like protein that has been shown to inhibit replication of several viruses including influenza, sindbis, herpes, HIV, HPV, and Ebola. ISG15 modification, called ISGylation, occurs on over 100 cellular proteins and is catalyzed by the sequential action of the interferon-inducible E1, E2, and E3 ubiquitin ligases called UBE1L, UbcH8/Ube2L6, and Herc5, respectively [12, 16•]. Unlike canonical ubiquitination that targets proteins for degradation, ISGylation can have

Viperin

Viperin is an ER-associated ISG that inhibits HCV, HCMV, influenza, and HIV-1 through several mechanisms. Wang et al. showed that Viperin disrupts cell plasma membrane and lipid raft integrity and inhibits influenza virion budding [22]. Overexpression of farnesyl diphosphate synthase (FPPS), an enzyme required for isoprenoid synthesis and lipid metabolism, reversed this antiviral effect, suggesting that Viperin prevents viral budding through inhibition of FPPS [22].

Viperin may inhibit HCV

Interferon inducible GTPases

Both type I and type II interferon significantly induce expression of the Mx, p47, and p65 families of GTPases, which hydrolyze GTP and are well-known to confer resistance against a wide range of pathogens. The Mx proteins inhibit replication of orthomyxoviruses, Thogoto virus, bunyaviruses and rhabdoviruses [11, 26]. The family of p47 GTPases, which consists of Iigp, Lrg47, Irg47, Tgtp, Iigp, and Gtpi, predominantly inhibits bacteria and protozoa growth [27]. Only Tgtp and Igtp overexpression

Concluding remarks

The complex host–virus interactions involved in mounting and executing an effective response to viral infections represent one of the major directions in innate immunity research. Although the general scheme for viral detection has been unraveled, much in terms of the actual ligands during an infection as well as the relative contribution of specific receptor signaling remains to be determined. One particularly important point will be defining the definitive detection pathway(s) for DNA viruses

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors were supported by funding from the National Institutes of Health (R01 AI069120, R01 AI078389 and PN2EY018228). We also thank the members of the Cheng laboratory for helpful discussions on the topic. We apologize for not recognizing authors who have made important contributions to the field of type I interferon induction and antiviral function due to reference limitation.

References (59)

  • D.A. Leib et al.

    Specific phenotypic restoration of an attenuated virus by knockout of a host resistance gene

    Proc Natl Acad Sci USA

    (2000)
  • L. Berthoux et al.

    Lv1 inhibition of human immunodeficiency virus type 1 is counteracted by factors that stimulate synthesis or nuclear translocation of viral cDNA

    J Virol

    (2004)
  • M. Pion et al.

    APOBEC3G/3F mediates intrinsic resistance of monocyte-derived dendritic cells to HIV-1 infection

    J Exp Med

    (2006)
  • D.J. Lenschow et al.

    IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses

    Proc Natl Acad Sci USA

    (2007)
  • K. Chin et al.

    Viperin (cig5), an IFN-inducible antiviral protein directly induced by human cytomegalovirus

    Proc Natl Acad Sci USA

    (2001)
  • T. Kawai et al.

    Toll-like receptor and RIG-1-like receptor signaling

    Ann N Y Acad Sci

    (2008)
  • A. Baum et al.

    Induction of type I interferon by RNA viruses: cellular receptors and their substrates

    Amino Acids

    (2010)
  • P. Yang et al.

    The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a [beta]-catenin-dependent pathway

    Nat Immunol

    (2010)
  • R. Stadeli et al.

    Transcription under the control of nuclear arm/[beta]-catenin

    Curr Biol

    (2006)
  • Z. Wang et al.

    Regulation of innate immune responses by DAI (DLM-1/ZBP1) and other DNA-sensing molecules

    Proceedings of the National Academy of Sciences

    (2008)
  • H. Ishikawa et al.

    STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling

    Nature

    (2008)
  • H. Ishikawa et al.

    STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity

    Nature

    (2009)
  • Y. Chiu et al.

    RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway

    Cell

    (2009)
  • R. Barbalat et al.

    Toll-like receptor 2 on inflammatory monocytes induces type I interferon in response to viral but not bacterial ligands

    Nat Immunol

    (2009)
  • O. Haller et al.

    Interferon-induced Mx proteins in antiviral host defense

    Biochimie

    (2007)
  • A.J. Sadler et al.

    Interferon-inducible antiviral effectors

    Nat Rev Immunol

    (2008)
  • A.G. Hovanessian

    On the discovery of interferon-inducible, double-stranded RNA activated enzymes: The 2’-5’oligoadenylate synthetases and the protein kinase PKR

    Cytokine & Growth Factor Reviews

    (2007)
  • A.L. Brass et al.

    The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and Dengue virus

    Cell

    (2009)
  • L.A. Durfee et al.

    The ISG15 conjugation system broadly targets newly synthesized proteins: implications for the antiviral function of ISG15

    Mol Cell

    (2010)
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