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INTERFERONS

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

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  1. INTERFERONS

  2. 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-) • 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

  3. How They Were Discovered (1957)

  4. Interferon Antiviral Activity

  5. 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

  6. 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

  7. 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

  8. Interferon Transcription Induction • The receptors that detect bacterial and viral antigens are called TLR (toll like receptors) • TLR3 detects dsRNA

  9. 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

  10. 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

  11. Interferon Signaling JAK JAK JAK

  12. 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

  13. 2',5' oligo(A) synthetase and ribonuclease L

  14. 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

  15. 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

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