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我的學思歷程 ～從冠狀病毒到肝炎病毒～

我的學思歷程 ～從冠狀病毒到肝炎病毒～. 賴明詔 Michael M.C. Lai 成功大學校長 April 17, 2009. 成功大學. 成立於 1931 於台南 （鄭成功 的故鄉 ) 工學院，理學院，文學院， 電機資訊，規劃設計，管理學院，醫學院，社會科學，生物科技學院 學生 : 20538 名 (10462 名大學生， 6948 名碩士， 3128 名博士 教授 : 1789 名 職員 : 3673 名 (1520 名於大學部， 2153 名於附設醫院 ) 台灣第二大大學 企業界最愛. 我的研究生涯.

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我的學思歷程 ～從冠狀病毒到肝炎病毒～

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  1. 我的學思歷程～從冠狀病毒到肝炎病毒～ 賴明詔 Michael M.C. Lai 成功大學校長 April 17, 2009

  2. 成功大學 • 成立於1931 於台南 （鄭成功 的故鄉) • 工學院，理學院，文學院， 電機資訊，規劃設計，管理學院，醫學院，社會科學，生物科技學院 學生: 20538名(10462名大學生，6948名碩士，3128名博士 教授: 1789名 職員: 3673名 (1520名於大學部，2153名於附設醫院) 台灣第二大大學 企業界最愛

  3. 我的研究生涯 • 大學時代 (台大 醫學院醫科) • 研究生時代 (加大柏克萊) • 大學教授時代 (南加大)腫瘤病毒　　冠狀病毒　 肝炎病毒 (D and C 型） • 回國(2003)後 中央研究院副院長 成功大學校長

  4. 病毒形狀

  5. 病毒形狀 (二)

  6. 廿面體的基本構造 Triangulation numbers 5-, 3-, 2x symmetry Quasisymmetry

  7. Structure of Calicivirus

  8. 病 毒 的 基 因 • ☼ 人 類 細 胞 有 3 萬 個 基 因 • ☼ 細 菌 有 5千 個 基 因 • ☼ 病 毒 有 10~100 個 基 因

  9. DNARNAProteins RNA The Central Dogma

  10. Retroviruses (RNA tumor viruses)(Viruses with reverse transcriptase) • Rous Sarcoma virus (Peter Duesberg, Harry Rubin) • RNA, glycoproteins, phosphoproteins • Oncogenes: src. • Rel (NFkB), erb, etc. (Peter Vogt)

  11. Demyelinating diseases • Multiple sclerosis: central nervous system demyelination (virus-induced autoimmune reaction) • Theiler’s encephalomyelitis virus (picornavirus) • Measles virus • Experimental allergic encephalitis (EAE) • Mouse hepatitis virus (MHV): Coronavirus

  12. Coronavirus （冠狀病毒)

  13. Multiple sclerosis多發性神經硬化Common colds傷風感冒SARS

  14. L 1 5 2 3 4 6 SARS a a b S M N b E (Proteases and RNA polymerase) I L 1 5 2 2-1 3 4 6 7 MHV a HE S E M N I L 1 5 2 3 4 6 IBV a a S M N b b E Genome structure of Coronavirus: 31-kb, single-strand, (+)-sense RNA

  15. MHV Genomic and Subgenomic RNAs POL HE S E M N (A)n 31 kb 1 2 3 4 5 6 7 ( Leader Intergenic Sequence 3'-UTR RNA recombination

  16. 台灣SARS病例

  17. 肝炎病毒 • A型 : 急性肝炎 Picornavirus • B 型 : 慢行肝炎(肝癌) Hepadnavirus • C 型 : 慢性肝炎 (肝癌) Flavivirus • D 型 : 慢性肝炎 Deltaviridae • E 型 : 急性肝炎Calicivirus

  18. Major protein Middle protein Large protein Hepatitis Delta Virus RNA HBsAg Nucleocapsid (HDAg) Phospholipid

  19. Challenges of Hepatitis Delta Virus • Viroid-like circular RNA with a protein • Make both full-length RNA replication and subgenomic mRNA transcription • Carry out RNA-dependent RNA transcription, but do not encode RNA-dependent polymerase: • Cellular RdRP?

  20. Hepatitis C virus • 170 million carriers in the world (2% of population) • Tendency to cause persistent infection, leading to chronic hepatitis, liver cirrhosis, hepatoma • A flavivirus with single-stranded RNA

  21. HBV (-), HCV (-) 1.0 HBV (+) 5.1 HCV (+) 22.3 HCV (+), HBV (+) 56.2 (Adapted from Yuan et al. [1999]) Hepatitis C virusRelative risks of hepatocellular carcinomain non-Asians of Los Angeles County

  22. HCV Genes and Gene products ER Lindenbach et al, Nature 933, 2005

  23. Life cycle of HCV Receptor Endosome Golgi ? rER ? ER or Golgi ? Nature436, 933-938 (18 August 2005 )

  24. HCV Genome and HCV Replicon R. Bartenschlager et al. / Antiviral Research 60 (2003) 91–102

  25. Clinical manifestations of HCV Liver: Asymptomatic or acute hepatitis  chronic hepatitis  liver cirrhosis  hepatocellular carcinoma B cells: Mixed cryoglobulinemia (B-cell oligoclonal proliferation) non-Hodgkin’s B-cell lymphoma Autoimmune diseases: Sjogren’s syndrome Pseudomembranous glomerulonephritis Purpura, Diabetes mellitus, thyroid disease

  26. HCV: A non-retroviral oncogenic RNA virus Hepatocellular Carcinoma Liver Cirrhosis Frequent Mutations of p53 (Teramoto et al., CancerRes.) HCV Chronic Infection Lymphoproliferative Diseases (mixed Cryoglobulinemia) B cell Lymphoma Hypermutation of Ig Ivanovski et al., Blood)

  27. Establishment of a B-cell lymphoma cell line (SB cells) • Established from the spleen of an HCV-positive patient with B-cell lymphoma and mixed cryoglobulinemia: proof that HCV infects B cells in vivo. • Produces infectious virus particles that are capable of infecting B cells but not hepatocytes. • The immunoglobulin gene is monoclonal but undergoes continuous evolution

  28. Electroporation into Huh7.5 and Raji Detection (qRT-PCR) Harvest In vitro Transcribed RNA Molecular mechanism of viral lympho- vs hepatotropism

  29. m m SB virus RNA, but not JFH-1 Virus, Replicates in Raji Cells Raji

  30. m m JFH-1 Virus, but not SB Virus RNA, Replicates in Huh7.5 Cells Huh7.5 • SB virus is lymphotropic. • JFH-1 virus is hepatotropic.

  31. HCV induces a mutator phenotype • HCV infection causes a 5-10-fold increase in mutation frequency of cellular genes, including immunoglobulin (Ig) and somatic genes, e.g., p53 or b-catenin genes. • Increased mutations are seen in in vitro HCV-infected B cells and in PBMC from HCV-infected individuals. • Mutations are amplified in the HCV-infected lymphoma and hepatoma.

  32. Mutation frequency (mutation/bp) x10-4 p53 -catenin Amplified oncogene mutations in HCV(+) B-cell tumors and hepatoma HCV-associated Non-HCV HCV tumor nontumor HBV tumor nontumor Nonviral tissues 30 3.9 35 5.9 3.9 0 2.5 33 0 30 11 7.4 7.4 4.4 B cell lymphomas Hepatocellular carcinomas (HCC)

  33. Mock HCV (+) HCV (-) DW A DSBs 872 603 234 B DSBs in VH C DSBs in p53 D VH E HCV RNA Raji JT F DSBs 872 603 MK - HCV+ - HCV+ 234 Double-stranded DNA breaks in HCV-infected cells (by linker-ligation PCR) MK 0 2 4 8 16 2 4 8 16 Day p.i.

  34. Challenges of Hepatitis C Virus • Vaccines • Therapy (interferon and ribavirin) • Mechanism of HCV pathogenesis (persistent infection) and oncogenesis • The mechanism of immune escape • The role of B and T cell infection

  35. Challenges of Infectious Diseases • Antibiotics • Small pox • Polio • Hepatitis B virus • Human papillomavirus • HIV • Malaria • Drug-resistant tuberculosis

  36. Emerging and reemerging infectious diseases HIV Measles SARS Avian flu Marburg Courtesy of Dr. Anthony Fauci, NIAID

  37. 大學生要學什麼 • 追求自己的興趣，不管「熱」或「冷」門 • 不怕選「錯」門 • 多嘗試新的領域 • 重視通識教育，培養人文藝術素養及品德 • 養成表達的能力

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