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Tumor Virology Course: MSMVM 3435, Dec 2, 2009.

Tumor Virology Course: MSMVM 3435, Dec 2, 2009. Who Am I?. Saumendra N. Sarkar, Ph.D. (Saumen) University of Pittsburgh Cancer Institute, HCC 1.8  5117 Centre Avenue, Pittsburgh, PA 15213  Phone: (412) 623-7720, Fax: (412) 623-7715 E-mail: saumen@pitt.edu

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Tumor Virology Course: MSMVM 3435, Dec 2, 2009.

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  1. Tumor Virology Course: MSMVM 3435, Dec 2, 2009. Who Am I? Saumendra N. Sarkar, Ph.D. (Saumen) University of Pittsburgh Cancer Institute, HCC 1.8 5117 Centre Avenue, Pittsburgh, PA 15213  Phone: (412) 623-7720, Fax: (412) 623-7715 E-mail: saumen@pitt.edu Web: http://labs.mmg.pitt.edu/sarkar/ What Am I going to talk about? And Why? • Innate Immunity, Inflammation and tumorigenesis. • Host responses to virus infection • Innate immune response to virus • Interferons (IFN) • Viral components and their Sensors • TLR, RLR, NLRs • Innate Immune evasion strategies of viruses

  2. Evolution of the “central dogma” for Cancer. Weinbarg, 2000 Karin, Mantovani, 2006.. • Examples: • Helicobacter pylori (Marshall & Warren, 2005) • Human papillomavirus (zur Hausen, 2008) • Hepatitis B and C virus

  3. Mechanisms of Inflammation mediated Cancer. Karin (2006) Cell. 124, 823 Montavani (2008) Nature. 454, 436

  4. Kinetics of immune response after virus infection Biron & Sen (2007) Fields Virology

  5. Interferons Type I (a1, a2.., b, d, e, t, k..) Type II (g)

  6. Transcription Factors: NF-kB, STAT and IRF

  7. IFN Signaling

  8. Protein Kinase RNA activated (PKR) Enzyme: Ser/Thr kinase, Activator dsRNA, PACT (cofactor) Substrate: eIF2a, PKR, other substrates in vitro. Function:Translation inhibition, other PKR Structure PKR Activation

  9. INTERFERON 2’-5’ OAS ATP dsRNA Inactive RNase L Active RNase L RNA Degradation 2’-5’ OligoadenylateSynthetases (OAS)

  10. Structure of OAS1 Hartmann, Sarkar et al. (2003) Mol Cell. 19, 1173

  11. Other ISGs ISG56 Family: Human ISG 56, 54, 60, aka IFIT Interaction with eIF3, translation inhibition ADAR: RNA-Specific Adenosine Deaminase Mx/GBP: small GTP binding proteins ISG15: Similar to Ubiquitin A || U I || U I || C

  12. Virus - dsRNA – Interferon – anti-viral state

  13. Interferon bEnhansosome PRD IV PRD III-I PRD II Escalante et al, Mol. Cell 26, 703-16

  14. Toll-like Receptors

  15. TLR Structures Jin et al, Immunity 29, 182-91

  16. NLRs, RLRs Inflammosomes PYD: Pyrin NACHT: used to be called NOD NOD: Nucleotide Oligomerization NAD: NACHT Associated CARD: Caspase Recruitment LRR: Leucine Rich Repeat BIR: Baculovirus IAP Repeat. Meylan et al, Nature 442, 39-44

  17. Cellular Sensors of DNA and DNA viruses • DNA transfection induces IFNb independent of TLRs (Stetson, 2005) • Cytoplasmic DNA sensor – DAI/ZBP1 (Takaoka, 2007) • Transient Expression allows DNA dependent IRF activation, siRNA. • DAI interaction with DNA • NALP3/ASC Inflammosome (Muruve, 2008) • Adenoviral particles, capsid, DNA induced IL-1 secretion in a NALP3, ASC dependent manner. • No IRF activation. • AIM2, new protein which interacts with ASC (Hornung, 2009) • Binding, localization with ASC • Direct DNA binding • IRF activation? • RNA polymerase III, transcribes dA.dT to RNA for RIG-I recognition (Hornung, 2009/Chen, 2009) • 5’pppN is important

  18. PRR Signaling Pathways

  19. TLR Signaling Pathways: Gene Induction

  20. RLR Signaling Pathways: Gene Induction Takeuchi and Akira Curr. Opin. Immun. 20, 17-22

  21. NLR Signaling Pathways: IL-1 Production & Gene Induction Meylan et al, Nature 442, 39-44

  22. Viral Evasion

  23. Strategies to evade host response Finlay et al, Cell 124, 767

  24. Examples of Viral Evasion TLR/RLR IFN ISG Pox V IFNARs IFNGRs TNFR Flu NS1 Paramyxo V, W HCV NS3/4A Adeno VAI RNA Mu V Nipah W Adeno VAI RNA EBV EBER RNA HIV TAR RNA Vaccinia E3L Adeno E1A EBNA1 HHV8 K9 HPV E6 Multifunctional viral proteins with multiple targets!! Paramyxo V and W, Flu NS1, Adeno E1A, SV40 T……

  25. Putting it together Natural Selection

  26. References • Innate Immunity, TLR, NLR • Immunity's Early-Warning System, Luke A. J. O'Neill, Scientific American, Jan 2005. (@ sarkarlab/research) • Recognition of microorganisms and activation of the immune response, Ruslan Medzhitov, Nature, Oct 18, 2007 (PMID: 17943118) • Akira, S., Uematsu, S., and Takeuchi, O. (2006) Pathogen recognition and innate immunity. Cell. 124, 783-801. (PMID: 16497588) • Infalammation Cancer • Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Michael Karin, Toby Lawrence, and Victor Nizet Cell 124 (4), 823-35 (PMID: 16497591) • Cancer-related inflammation. Mantovani A, Allavena P, Sica A, Balkwill F. Nature. 454: 436 (PMID: 18650914) • Viral Evasion • Pathogen subversion of cell-intrinsic innate immunity. Roy CR, Mocarski ES. Nat Immunol. 8:1179 (PMID: 17952043) • Viral evasion and subversion of pattern-recognition receptor signalling. Bowie AG, Unterholzner L. Nat Rev Immunol. 8: 911(PMID: 18989317)

  27. My Assessment • I think it was pretty good. • How to keep people falling off to sleep? • Make people more interactive during the class • Incorporate more stories and experiments describing how some of these were discovered.

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