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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.

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Presentation on theme: "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."— Presentation transcript:

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2 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

3 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 : 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

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6 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

7 病毒形狀

8 病毒形狀 ( 二 )

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

10 Structure of Calicivirus

11 病 毒 的 基 因病 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

12 The Central Dogma DNA RNA Proteins RNA

13 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)

14 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

15 Coronavirus (冠狀病毒 )

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

17 Genome structure of Coronavirus: 31-kb, single-strand, (+)-sense RNA

18 HESEMN (A)n 31 kb POL MHV Genomic and Subgenomic RNAs ( Leader Intergenic Sequence 3'-UTR RNA recombination

19 台灣 SARS 病例

20 肝 炎 病 毒肝 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

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

22 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?

23 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

24 Hepatitis C virus Relative risks of hepatocellular carcinoma in non-Asians of Los Angeles County HBV (-), HCV (-)1.0 HBV (+)5.1 HCV (+)22.3 HCV (+), HBV (+)56.2 (Adapted from Yuan et al. [1999])

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

26 Life cycle of HCV Nature 436, (18 August 2005 ) ER or Golgi ? rER ? Endosome Receptor Golgi ?

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

28 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

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

30 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

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

32 SB virus RNA, but not JFH-1 Virus, Replicates in Raji Cells   Raji

33 JFH-1 Virus, but not SB Virus RNA, Replicates in Huh7.5 Cells   Huh7.5 SB virus is lymphotropic. JFH-1 virus is hepatotropic.

34 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  -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.

35 Amplified oncogene mutations in HCV(+) B-cell tumors and hepatoma B cell lymphomas Hepatocellular carcinomas (HCC) HCV-associated Non-HCV HCV tumor nontumor HBV tumor nontumor Nonviral tissues Mutation frequency (mutation/bp) x10 -4 p53  -catenin

36 MK Day p.i. Raji JT DSBs VHVH HCV RNA Mock HCV (+) HCV (-) DW MK - HCV+ - HCV+ D C B A E F DSBs in V H DSBs in p53 DSBs Double-stranded DNA breaks in HCV- infected cells (by linker-ligation PCR)

37 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

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

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

40 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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