Immune response - Antiviral actions of Interferons

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Antiviral actions of Interferons

Interferons (IFNs) are widely expressed cytokines. They modulate antiviral, antiproliferative and immunomodulatory functions of the cells. The IFN family includes two main classes of related cytokines: type I IFNs and type II IFN. There are many type I IFNs, including IFN-alpha (having several subtypes of its own) and IFN-beta. All type I IFNs bind a common two-subunit cell-surface receptor known as the type I IFN receptor,or IFN-alpha/beta receptor. By contrast, there is only one type II IFN, IFN-gamma, that binds to another receptor, IFN-gamma receptor, also a two-subunit protein.

The interaction between IFN receptors and kinases of the Janus activated kinase (JAK) family is critical for signaling by IFNs. Ligand binding to receptors produces oligomerization of receptor subunits and results in the activation of cytoplasmic JAKs that bind to the membrane-proximal domain of specific IFN receptor subunits. IFN-alpha/beta receptor interacts with the Janus activated kinases Tyk2 and JAK1. IFN-gamma receptor interacts with JAK1 and JAK2. Activation of the JAKs associated with the IFN-alpha/beta receptor results in tyrosine phosphorylation of signal transducers and activators of transcription STAT1 and STAT2; this leads to the formation of the complex between STAT1, STAT2 and IFN-regulatory factor 9 (IRF9) that is known as IFN-stimulated gene factor 3 complex (ISGF3). This complex translocates to the nucleus, binds IFN-stimulated response elements (ISREs) and initiates gene transcription. Both type I and type II IFNs also induce the formation of STAT1-STAT1 homodimer. The latter translocates to the nucleus and binds IFN-gamma-activated site (GAS) elements in promoter sequences of certain genes, thus initiating their transcription [1].

Transcription factors of the Interferon regulatory factor (IRF) family are also important regulators in the IFN response. IRF1 binds directly to the ISRE found in the promoter of IFN-alpha/beta-regulated genes and plays an important role in the antiviral actions of the IFNs.

IRF3, a key transcriptional activator affected by viral infection, is constitutively expressed in many cells and tissues, and its activation leads to the prior induction of the IFN-alpha and IFN-beta genes. IRF3 is a subunit of the double-stranded RNA (dsRNA)-activated transcription factor complex that is directly activated by dsRNA or by virus infection. Activation of IRF3 results in its cytoplasmic-to-nuclear translocation and interaction with p300/CBP co-activators, leading to the transcriptional activation of the IFN-alpha and IFN-beta promoters [2].

The following IFN-induced proteins are implicated in the antiviral actions of IFNs in virus-infected cells: dsRNA-activated protein kinase (PKR), the 2,5-oligoadenylate synthetase (OAS) family and RNaseL nuclease, Adenosine deaminase (ADAR1), the family of Mx protein GTPases (including MxA), Indoleamine 2,3-dioxygenase (INDO), and Inducible Nitric Oxide Synthase (iNOS) [2].

IFN-inducible PKR is activated by autophosphorylation. This process is initiated by the double-stranded RNA. PKR inhibits viral mRNA translation through the phosphorylation of Eukaryotic translation initiation factor 2, subunit 1 alpha (EIF2S1), a subunit of the translation initiation factor eIF2 that catalyzes the first regulated step of the protein synthesis initiation and promotes the binding of the initiator tRNA to 40S ribosomal subunits [3].

OAS (OAS1, OAS2 and OAS3 synthetases) catalyze the synthesis of oligoadenylates of the general structure ppp(A2'p)nA (or 2-5A oligoadenylate). RNaseL, a latent endoribonuclease, becomes activated by binding 2-5A oligoadenylate. RNaseL mediates mRNA degradation. The RNaseL inhibitor (RLI) is believed to regulate OAS and RNaseL activity via the formation of a latent heterodimeric protein complex [4], [5].

RNA-specific adenosine deaminase ADAR1, a protein inducible by IFN-alpha, is implicated in the editing of viral RNA transcripts and cellular pre-mRNAs. ADAR1 catalyzes the covalent modification of RNA substrates by hydrolytic deamination of adenosine to yield inosine. The resultant transitions destabilize the double-stranded RNA helix by disruption base pairing [2], [6], [7].

The Mx protein GTPases (especially cytoplasmic MxA) appear to target viral nucleocapsids, inhibit RNA synthesis and block viral replication [1].

Tryptophanyl-tRNA synthetase (WARS) catalyzes the aminoacylation of tRNA with (L)-tryptophan, leading to the binding of (L)-tryptophan to tRNA, (L)-tryptophan*(tRNA) formation and viral protein synthesis [8]. Indoleamine 2,3-dioxygenase (INDO) is the rate-limiting enzyme in the kynurenine (N-formyl-kynurenine) pathway of (L)-tryptophan metabolism. INDO-mediated (L)-tryptophan deprivation protects cells by inhibiting the replication of a variety of pathogens including viruses [9].

In addition to antiviral effects exerted at the single-cell level that reduce viral synthesis, IFNs modulate a number of immunoregulatory cell functions. Nitric Oxide Synthase (iNOS), which is inducible by IFN-gamma, catalyzes NADPH-dependent oxidation of (L)-arginine to yield nitric oxide (NO) and citrulline. NO plays an important role in the host response to infection and inhibition of virus replication.

The major histocompatibility complex (MHC) MHC class I and MHC class II molecules present the antigenic peptides derived from proteolysis of foreign viral protein antigens, to the cytotoxic T cells. Virus-specific recognition and killing of infected cells are key components of the host defense to viral infection. Both IFN-alpha/beta and IFN-gamma induce MHC class I expression, and IRF1 plays a key role in transcription of these genes. MHC class II transactivator factor (CIITA) is the master regulator of MHC class II expression that is efficiently induced by IFN-gamma. Notably, CIITA also co-regulates the transcription of MHC class I. Most cell types do not express basal CIITA. Expression of CIITA is inducible by IFN-gamma [2], [10].

References:

  1. Platanias LC
    Mechanisms of type-I- and type-II-interferon-mediated signalling. Nature reviews. Immunology 2005 May;5(5):375-86
  2. Samuel CE
    Antiviral actions of interferons. Clinical microbiology reviews 2001 Oct;14(4):778-809, table of contents
  3. Anderson P, Kedersha N
    Visibly stressed: the role of eIF2, TIA-1, and stress granules in protein translation. Cell stress & chaperones 2002 Apr;7(2):213-21
  4. Bisbal C, Salehzada T, Silhol M, Martinand C, Le Roy F, Lebleu B
    The 2-5A/RNase L pathway and inhibition by RNase L inhibitor (RLI). Methods in molecular biology (Clifton, N.J.) 2001;160:183-98
  5. Sen GC, Lengyel P
    The interferon system. A bird's eye view of its biochemistry. The Journal of biological chemistry 1992 Mar 15;267(8):5017-20
  6. George CX, Wagner MV, Samuel CE
    Expression of interferon-inducible RNA adenosine deaminase ADAR1 during pathogen infection and mouse embryo development involves tissue-selective promoter utilization and alternative splicing. The Journal of biological chemistry 2005 Apr 15;280(15):15020-8
  7. Taylor DR, Puig M, Darnell ME, Mihalik K, Feinstone SM
    New antiviral pathway that mediates hepatitis C virus replicon interferon sensitivity through ADAR1. Journal of virology 2005 May;79(10):6291-8
  8. Shen N, Guo L, Yang B, Jin Y, Ding J
    Structure of human tryptophanyl-tRNA synthetase in complex with tRNATrp reveals the molecular basis of tRNA recognition and specificity. Nucleic acids research 2006;34(11):3246-58
  9. Mellor AL, Munn DH
    IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nature reviews. Immunology 2004 Oct;4(10):762-74
  10. van den Elsen PJ, Holling TM, Kuipers HF, van der Stoep N
    Transcriptional regulation of antigen presentation. Current opinion in immunology 2004 Feb;16(1):67-75

  1. Platanias LC
    Mechanisms of type-I- and type-II-interferon-mediated signalling. Nature reviews. Immunology 2005 May;5(5):375-86
  2. Samuel CE
    Antiviral actions of interferons. Clinical microbiology reviews 2001 Oct;14(4):778-809, table of contents
  3. Anderson P, Kedersha N
    Visibly stressed: the role of eIF2, TIA-1, and stress granules in protein translation. Cell stress & chaperones 2002 Apr;7(2):213-21
  4. Bisbal C, Salehzada T, Silhol M, Martinand C, Le Roy F, Lebleu B
    The 2-5A/RNase L pathway and inhibition by RNase L inhibitor (RLI). Methods in molecular biology (Clifton, N.J.) 2001;160:183-98
  5. Sen GC, Lengyel P
    The interferon system. A bird's eye view of its biochemistry. The Journal of biological chemistry 1992 Mar 15;267(8):5017-20
  6. George CX, Wagner MV, Samuel CE
    Expression of interferon-inducible RNA adenosine deaminase ADAR1 during pathogen infection and mouse embryo development involves tissue-selective promoter utilization and alternative splicing. The Journal of biological chemistry 2005 Apr 15;280(15):15020-8
  7. Taylor DR, Puig M, Darnell ME, Mihalik K, Feinstone SM
    New antiviral pathway that mediates hepatitis C virus replicon interferon sensitivity through ADAR1. Journal of virology 2005 May;79(10):6291-8
  8. Shen N, Guo L, Yang B, Jin Y, Ding J
    Structure of human tryptophanyl-tRNA synthetase in complex with tRNATrp reveals the molecular basis of tRNA recognition and specificity. Nucleic acids research 2006;34(11):3246-58
  9. Mellor AL, Munn DH
    IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nature reviews. Immunology 2004 Oct;4(10):762-74
  10. van den Elsen PJ, Holling TM, Kuipers HF, van der Stoep N
    Transcriptional regulation of antigen presentation. Current opinion in immunology 2004 Feb;16(1):67-75

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