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INTERFERONS. Interferons. Interferons are proteins, immunologist prefer to call them cytokines They are glycosylated The name originates from the fact that they interfere with viral infection 2 types exist Type I (IFN- , 13 different alleles exist in an individual and IFN-  )

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  • Interferons are proteins, immunologist prefer to call them cytokines
    • They are glycosylated
  • The name originates from the fact that they interfere with viral infection
  • 2 types exist
    • Type I (IFN-, 13 different alleles exist in an individual and IFN-)
    • Type II (IFN-)
  • Cells producing IFNs
    • Plasmacytoid DCs (major producers of IFN-  and IFN- )
    • Fibroblasts and epithelial cells
    • Macrophages and Th1 Cells (predominantly IFN- )
  • Type I are stable at pH=2
  • Type II are unstable at pH=2 they are referred to as labile
interferons as therapeutic agents
Interferons As Therapeutic Agents
  • Currently recombinant pegylated interferons used in HCV and HBV infections
    • Pegintron (IFN--2b, Schering Plough) and Pegasys (IFN--2a, Roche) used in conjuction with Ribavirin (nucleoside analog similar to D-ribose)
    • Pharma claims 50% effectiveness in either lowering or pushing viral load below detection (in conjuction with Ribavirin)
    • They cause serious side effects such as depression and anemia
    • Risk of antibody production against pegylated interferon always a possibility
    • Effectiveness of interferons is more evident before viral infection has spread
interferon variation
Interferon Variation
  • 13 different IFN- alleles
    • Similar in a/a sequence
    • A lot of variation in glycosylation
    • Same a/a number
    • Produced a variety of cells, champion though is pDC
  • IFN- one gene
    • Produced by fibroblasts and epithelial cells
    • Also pDCs
  • IFN- (Type II)
    • Produced by Th1 and M
    • More of an immunomodulator rather than anti-viral agent
    • 2 versions secreted, differ only in glycosylation
interferon transcription induction
Interferon Transcription Induction
  • Best inducer is viral infection
  • dsRNA viruses are exceptionally good at inducing IFN production
  • Synthetic dsRNA can do the same thing suggesting that viral infection and subsequent exposure to dsRNA is what triggers IFN production
  • You do not have to be dsRNA virus to produce dsRNA
interferon transcription induction8
Interferon Transcription Induction
  • The receptors that detect bacterial and viral antigens are called TLR (toll like receptors)
  • TLR3 detects dsRNA
transcription factors that induce ifn expression
Transcription Factors That Induce IFN Expression
  • Uninfected cells do not express IFNs
    • Strong suppression of promoters and enhancers
  • IFN/ relies on positive regulatory domains (PRDs)
    • These domains are binding sites for transcription factors
    • These domains are 200 nt upstream transcription start site
    • A well studied enhancer is the IFN- (enhancer is made up of a number of PRDs)
  • All the proteins together with TFIID and Pol II form the enchanceosome
  • 9 IRFs are known
  • Recently HSV was found to produce IRF look alike avoiding expression of IFNs
interferon signaling
Interferon Signaling
  • Interferon signaling mediated thru JAKs and STATS
    • JAKs (Janus Kinases) or just another kinase!
    • STATS (Signal transducers and activators of transcription)
  • The JAK/STAT pathway utilized by other cytokines as well
  • Binding of Interferon to receptor causes receptor dimerization
  • JAKs associate to receptor before interferon binding
    • Binding causes them to get activated and phosphorylate receptor and collaborating JAKs
  • Phosphorylated receptors behave as docking sites for STATs
  • JAKs phosphorylate STATs once they dock to receptors
  • Phosphorylated STATs dimerize and translocate to nucleus
  • JAK-STAT pathway is extremely rapid
    • STAT binding to DNA can be detected within minutes of interferon receptor binding
  • Over 100 genes can be induced via interferon signaling
  • Rapidity is needed to respond to danger
interferons provide first line of defense against viral infection
Interferons Provide First Line of Defense Against Viral Infection
  • Interferon release is part of innate immunity
  • Adaptive immunity kicks in at a later point
  • IFN has been shown to block entry and uncoating of viruses
  • However its best understood anti-viral mechanism is:
    • 1. Block viral mRNA synthesis
    • 2. Block translation of viral mRNA
  • Three anti-viral systems are being studied and party understood at this point
    • Mx proteins
    • 2',5' oligo(A) synthetase and ribonuclease L
    • PKR, double stranded RNA dependent protein kinase
  • Mx proteins (myxovirus proteins) are induced by interferon
    • They can hydrolyze GTP
    • Block viral RNA polymerase
    • Block transport of viral nucleoproteins (influenza virus) into nucleus
      • How it is done is unclear at this point
  • 2',5' oligo(A) synthetase and ribonuclease L
    • This enzyme gets activated by dsRNA
    • Unique ability to synthesize oligos of A in the 2'- 5' linkage, norm is 3'-5' linkage
    • Poly(A) oligos bind ribonuclease L and activate it  mRNA is destroyed
    • Both cellular and viral
    • Cell may die due to this activity though
anti viral mechanisms
Anti-Viral Mechanisms
  • PKR (dsRNA dependent protein kinase)
    • PKR expression increases after IFN treatment
    • PKR activated by dsRNA
  • 2 PKRs bind to same dsRNA and phosphorylate each other
  • PKR kinase activity increases and targets proteins
    • The best known target protein is eIF2
    • Phosphorylated eIF2 cannot initiate translation
    • Both cellular and viral translation is inhibited
    • PKR also causes apoptosis
viruses evade interferon response
Viruses Evade Interferon Response
  • Viruses adapt to the interferon response by making proteins that neutralize PKR
  • Adenoviruses Evasion Mechanisms
    • They produce VI A RNA (160 nt long) that binds PKR
    • This RNA takes double stranded form
    • However PKR does not get activated
    • No eIF2 phosphorylation
    • Translation proceeds as expected
    • Adenoviruses also produce E1A which sequesters p300/CPB
      • These are needed for interferon expression, they are co-factors
  • Epstein Barr Virus encodes for RNA that acts in similar manner