我的學思歷程 ~從冠狀病毒到肝炎病毒~
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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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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
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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
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病毒形狀
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病毒形狀 (二 )
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廿面體的基本構造
Triangulation numbers
5-, 3-, 2x symmetry
Quasisymmetry
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Structure of Calicivirus
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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
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The Central Dogma
DNA RNA Proteins
RNA
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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)
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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
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Coronavirus (冠狀病毒 )
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Multiple sclerosis 多發性神經硬化
Common colds 傷風感冒
SARS
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Genome structure of Coronavirus:31-kb, single-strand, (+)-sense RNA
MHV
IBV
SARS
L 12 2-1 3 4
56 7
(Proteases and RNA polymerase)
HE S E M N
I
a
L 12 3 54 6
SE
M Nab
ab
L 12 3 54 6
SE
M N
Ib
a ba
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HE S E M N(A)n 31 kb
POL
MHV Genomic and Subgenomic RNAs
1 2 3 4 5 6 7
(Leader
Intergenic Sequence
3'-UTR
RNA recombination
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台灣 SARS 病例
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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
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Hepatitis Delta Virus
RNA
Nucleocapsid(HDAg)
HBsAg
Majorprotein
Middleprotein
Largeprotein
Phospholipid
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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?
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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
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Hepatitis C virus
Relative risks of hepatocellular carcinomain 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])
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HCV Genes and Gene products
Lindenbach et al, Nature 933, 2005
ER
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Life cycle of HCV
Nature 436, 933-938 (18 August 2005 )
ER or Golgi ?
rER ?
Endosome
Receptor
Golgi ?
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HCV Genome and HCV Replicon
R. Bartenschlager et al. / Antiviral Research 60 (2003) 91–102
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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 syndromePseudomembranous glomerulonephritis
Purpura, Diabetes mellitus, thyroid disease
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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
LymphoproliferativeDiseases (mixed Cryoglobulinemia)
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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
•
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Molecular mechanism of viral lympho- vs hepatotropism
Harvest
Detection (qRT-PCR)
In vitro Transcribed RNA
Electroporation into Huh7.5 and Raji
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SB virus RNA, but not JFH-1 Virus, Replicates in Raji Cells
1.0E+00
1.0E+01
1.0E+02
1.0E+03
1.0E+04
1.0E+05
1.0E+06
1.0E+07
1.0E+08
1.0E+09
4 8 12 16 20 24 28 42 56 80 96
Day
HC
V R
NA
(c
op
ies
/ug
RN
A) JFH-1
JFH-1 GND 1b SB SB GND
1.0E+00
1.0E+01
1.0E+02
1.0E+03
1.0E+04
1.0E+05
1.0E+06
1.0E+07
1.0E+08
1.0E+09
4 8 12 16 20 24 28 42 56 80 96
Day
HC
V R
NA
(co
pie
s/u
g R
NA
)
JFH-1
JFH-1 GND
1b
SB
SB GND
Raji
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JFH-1 Virus, but not SB Virus RNA, Replicates in Huh7.5 Cells
1.0E+00
1.0E+01
1.0E+02
1.0E+03
1.0E+04
1.0E+05
1.0E+06
1.0E+07
1.0E+08
1.0E+09
4 8 12 16 20 24 28 42 56 80 96
Day
HC
V R
NA
(co
pie
s/u
g R
NA
) JFH-1 JFH-1-GND
1b
SB SB GND
1.0E+00
1.0E+01
1.0E+02
1.0E+03
1.0E+04
1.0E+05
1.0E+06
1.0E+07
1.0E+08
1.0E+09
4 8 12 16 20 24 28 42 56 80 96
Day
HC
V R
NA
(co
pie
s/u
g R
NA
) JFH-1 JFH-1-GND 1b SB SB GND
Huh7.5
•SB virus is lymphotropic.•JFH-1 virus is hepatotropic.
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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.
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Amplified oncogene mutations in HCV(+) B-cell tumors and hepatoma
B celllymphomas
Hepatocellularcarcinomas(HCC)
30 3.9
35 5.9
3.90
2.5
HCV-associatedNon-HCV
HCV tumor nontumor
HBV tumor nontumor
Nonviral tissues
Mutation frequency(mutation/bp) x10-4
p53 -catenin
33 0
30 11
7.4 7.4
4.4
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MK 0 2 4 8 16 2 4 8 16 Day p.i.
Raji JT
DSBs
VH
HCV RNA
Mock HCV (+) HCV (-) DW
MK - HCV+ - HCV+
D
C
B
A
E
F
DSBs in VH
DSBs in p53
DSBs
872 603 234
872 603
234
Double-stranded DNA breaks in HCV-infected cells (by linker-ligation PCR)
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Challenges of Hepatitis C Virus
VaccinesTherapy (interferon and ribavirin)Mechanism of HCV pathogenesis
(persistent infection) and oncogenesis The mechanism of immune escape The role of B and T cell infection
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Challenges of Infectious Diseases
Antibiotics Small pox Polio
Hepatitis B virus Human papillomavirus
HIV Malaria Drug-resistant tuberculosis
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Emerging and reemerging infectious diseases
Courtesy of Dr. Anthony Fauci, NIAID
SARS
Avian flu
HIV
Marburg
Measles
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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