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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳培哲(Pei-Jer Chen) | |
| dc.contributor.author | Yun-Hua Lin | en |
| dc.contributor.author | 林昀樺 | zh_TW |
| dc.date.accessioned | 2021-06-17T04:43:21Z | - |
| dc.date.available | 2020-10-03 | |
| dc.date.copyright | 2018-10-03 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-08-03 | |
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Replicating hepatitis delta virus RNA is edited in the nucleus by the small form of ADAR1. Proc Natl Acad Sci U S A 99, 15118-15123, doi:10.1073/pnas.232416799 (2002). 29 O'Malley, B. & Lazinski, D. W. Roles of carboxyl-terminal and farnesylated residues in the functions of the large hepatitis delta antigen. J Virol 79, 1142-1153, doi:10.1128/JVI.79.2.1142-1153.2005 (2005). 30 Kuo, M. Y., Chao, M. & Taylor, J. Initiation of replication of the human hepatitis delta virus genome from cloned DNA: role of delta antigen. J Virol 63, 1945-1950 (1989). 31 Fu-Lin Chang, P.-J. C., Su-Jen Tu, Chuan-Jen Wang, and Ding-Shinn Chen. The Large Form of Hepatitis δ Antigen Is Crucial for Assembly of Hepatitis δ Virus. Proc Natl Acad Sci U S A 88, 8490-8494 (1991). 32 Lee, C. Z., Chen, P. J. & Chen, D. S. Large hepatitis delta antigen in packaging and replication inhibition: role of the carboxyl-terminal 19 amino acids and amino-terminal sequences. J Virol 69, 5332-5336 (1995). 33 Flores, R. et al. Rolling-circle replication of viroids, viroid-like satellite RNAs and hepatitis delta virus: variations on a theme. RNA Biol 8, 200-206 (2011). 34 Taylor, J. M. Hepatitis delta virus. Virology 344, 71-76, doi:10.1016/j.virol.2005.09.033 (2006). 35 Taylor, J. M. Hepatitis D Virus Replication. Cold Spring Harb Perspect Med 5, doi:10.1101/cshperspect.a021568 (2015). 36 Kuo, M. Y., Sharmeen, L., Dinter-Gottlieb, G. & Taylor, J. Characterization of self-cleaving RNA sequences on the genome and antigenome of human hepatitis delta virus. J Virol 62, 4439-4444 (1988). 37 Sharmeen, L., Kuo, M. Y., Dinter-Gottlieb, G. & Taylor, J. Antigenomic RNA of human hepatitis delta virus can undergo self-cleavage. J Virol 62, 2674-2679 (1988). 38 Wu, H. N. et al. Human hepatitis delta virus RNA subfragments contain an autocleavage activity. Proc Natl Acad Sci U S A 86, 1831-1835 (1989). 39 Ferre-D'Amare, A. R., Zhou, K. & Doudna, J. A. Crystal structure of a hepatitis delta virus ribozyme. Nature 395, 567-574, doi:10.1038/26912 (1998). 40 Watanabe, T. et al. Involvement of host cellular multivesicular body functions in hepatitis B virus budding. Proc Natl Acad Sci U S A 104, 10205-10210, doi:10.1073/pnas.0704000104 (2007). 41 Chang, M. F., Chen, C. J. & Chang, S. C. Mutational analysis of delta antigen: effect on assembly and replication of hepatitis delta virus. J Virol 68, 646-653 (1994). 42 Galle, P. R. et al. In vitro experimental infection of primary human hepatocytes with hepatitis B virus. Gastroenterology 106, 664-673 (1994). 43 Gripon, P. et al. Infection of a human hepatoma cell line by hepatitis B virus. Proc Natl Acad Sci U S A 99, 15655-15660, doi:10.1073/pnas.232137699 (2002). 44 Sureau, C. The use of hepatocytes to investigate HDV infection: the HDV/HepaRG model. Methods Mol Biol 640, 463-473, doi:10.1007/978-1-60761-688-7_25 (2010). 45 Nakabayashi, H., Taketa, K., Miyano, K., Yamane, T. & Sato, J. Growth of human hepatoma cells lines with differentiated functions in chemically defined medium. Cancer Res 42, 3858-3863 (1982). 46 Morris, K. M., Aden, D. P., Knowles, B. B. & Colten, H. R. Complement biosynthesis by the human hepatoma-derived cell line HepG2. J Clin Invest 70, 906-913 (1982). 47 Gripon, P., Diot, C. & Guguen-Guillouzo, C. Reproducible high level infection of cultured adult human hepatocytes by hepatitis B virus: effect of polyethylene glycol on adsorption and penetration. Virology 192, 534-540, doi:10.1006/viro.1993.1069 (1993). 48 Yang, J. & Shen, M. H. Polyethylene glycol-mediated cell fusion. Methods Mol Biol 325, 59-66, doi:10.1385/1-59745-005-7:59 (2006). 49 Zeisel, M. B. et al. Towards an HBV cure: state-of-the-art and unresolved questions--report of the ANRS workshop on HBV cure. Gut 64, 1314-1326, doi:10.1136/gutjnl-2014-308943 (2015). 50 Allweiss, L. & Dandri, M. Experimental in vitro and in vivo models for the study of human hepatitis B virus infection. 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Sci Rep 5, 17047, doi:10.1038/srep17047 (2015). 56 Wu, J. C. Functional and clinical significance of hepatitis D virus genotype II infection. Curr Top Microbiol Immunol 307, 173-186 (2006). 57 Chang, S. Y. et al. Molecular epidemiology of hepatitis D virus infection among injecting drug users with and without human immunodeficiency virus infection in Taiwan. J Clin Microbiol 49, 1083-1089, doi:10.1128/JCM.01154-10 (2011). 58 Wang, T. C. & Chao, M. Molecular cloning and expression of the hepatitis delta virus genotype IIb genome. Biochem Biophys Res Commun 303, 357-363 (2003). 59 Lin, F. M., Lee, C. M., Wang, T. C. & Chao, M. Initiation of RNA replication of cloned Taiwan-3 isolate of hepatitis delta virus genotype II in cultured cells. Biochem Biophys Res Commun 306, 966-972 (2003). 60 Hsu, S. C. et al. Varied assembly and RNA editing efficiencies between genotypes I and II hepatitis D virus and their implications. Hepatology 35, 665-672, doi:10.1053/jhep.2002.31777 (2002). 61 Wang, C. J., Chen, P. J., Wu, J. C., Patel, D. & Chen, D. S. Small-form hepatitis B surface antigen is sufficient to help in the assembly of hepatitis delta virus-like particles. J Virol 65, 6630-6636 (1991). 62 Huang, L. R., Wu, H. L., Chen, P. J. & Chen, D. S. An immunocompetent mouse model for the tolerance of human chronic hepatitis B virus infection. Proc Natl Acad Sci U S A 103, 17862-17867, doi:10.1073/pnas.0608578103 (2006). 63 Mu, J. J., Chen, D. S. & Chen, P. J. The conserved serine 177 in the delta antigen of hepatitis delta virus is one putative phosphorylation site and is required for efficient viral RNA replication. J Virol 75, 9087-9095, doi:10.1128/JVI.75.19.9087-9095.2001 (2001). 64 Schulze, A., Mills, K., Weiss, T. S. & Urban, S. Hepatocyte polarization is essential for the productive entry of the hepatitis B virus. Hepatology 55, 373-383, doi:10.1002/hep.24707 (2012). 65 Modahl, L. E. & Lai, M. M. The large delta antigen of hepatitis delta virus potently inhibits genomic but not antigenomic RNA synthesis: a mechanism enabling initiation of viral replication. J Virol 74, 7375-7380 (2000). 66 Mu, J. J. et al. Characterization of the phosphorylated forms and the phosphorylated residues of hepatitis delta virus delta antigens. J Virol 73, 10540-10545 (1999). | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70908 | - |
| dc.description.abstract | 全球有大約1500-2000萬人口同時感染B型肝炎病毒以及D型肝炎病毒。D型肝炎病毒是B型肝炎病毒的衛星病毒，因為其需要B型肝炎病毒的表面蛋白當作外病毒的套膜，同時感染這兩種病毒比起只感染B型肝炎會更容易進展為最嚴重的肝炎，也就是猛爆型肝炎，猛爆型肝炎會使肝臟細胞快速死亡，更甚者則導致肝衰竭，因為D型肝炎病毒是在感染動物的病毒當中，所含基因最少的病毒，而這個基因也只能做出D型肝炎病毒唯一的蛋白，也就是delta抗原，然而delta抗原並非病毒複製所需的酵素，也不具複製酵素的活性，所以D型肝炎病毒必須利用宿主細胞因子或酵素來幫助其完成生命週期。研究D型肝炎病毒與宿主細胞之間的交互作用有希望能找出治癒D型肝炎的解藥，因此需要建立D型肝炎病毒的細胞感染模型。在先前的研究中，人類肝臟細胞(PHH)和HepaRG 細胞 (HepaRG cell)皆被用來當成細胞感染模型來研究，然而因為細胞不易取得，不易培養，使得實驗難以控制及重覆，直到發現鈉離子牛磺膽酸共運轉蛋白(NTCP)是B型肝炎病毒及D型肝炎病毒進入細胞的接受器，並且實驗也顯示大量表現鈉離子牛磺膽酸共運轉蛋白在細胞株上能夠使B型肝炎病毒及D型肝炎病毒更容易感染細胞。然而直接感染D型肝炎病毒在大量表現鈉離子牛磺膽酸共運轉蛋白的細胞株的結果並不理想，甚至不到百分之一的感染率，為了提升感染率，我嘗試了許多方法，像是細胞懸浮感染、病毒感染時加入二甲基亞碸(DMSO)和聚乙二醇(PEG8000)，甚至用了不同質體所產生的病毒株。總體來說，我將D型肝炎病毒的感染率提升至約三成，並且在這個細胞感染模式中可以測得D型肝炎病毒感染後產生的delta 抗原、基因體(genomic RNA)與反基因體(antigenomic RNA)。將感染率提升至此，我可以利用這個細胞感染模式來進一步做研究，首先，我在細胞感染模式上感染了不同基因型的D型肝炎病毒，以測試病毒感染力，研究發現基因型I感染力最好，基因型IV次之，基因型II最弱。未來，這個細胞感染模式能夠用來繼續研究D型肝炎病毒與細胞的相互作用，並且找出D型肝炎的解藥。 | zh_TW |
| dc.description.abstract | There are 15-20 million people worldwide chronically coinfected with Hepatitis delta virus (HDV) and Hepatitis B virus (HBV). Simultaneous infection of HBV and HDV may progress easier into the most severe form of hepatitis, fulminant hepatitis, than infection of HBV only. Fulminant hepatitis causes rapid death of hepatocytes and liver failure. HDV is a satellite virus of HBV and requires HBV surface proteins (HBs Ag) to serve as viral envelopes. Since HDV is the smallest virus in animal and encodes only one protein, delta antigen, which does not possess the activity to replicate HDV genome, it must utilize host enzymes or other host factors to fulfill its life cycle. To study the role of host factors in HDV life cycle, researchers use primary human hepatocytes (PHH) and HepaRG cells in cell infection model. However, limited supply and difficult management of these cells render experiments hard to be manipulated and reproduced. The discovery of sodium-taurocholate cotransporting polypeptide (NTCP) as a HBV or HDV receptor opens a gate for researchers. Some studies indicate that overexpression of hNTCP makes cells susceptible to HBV or HDV infection. However, HDV infection rate is less than 1% even in hNTCP-overexpressing hepatoma cell line. In order to optimize the infection model in our laboratory, I used suspension infection, treatment of DMSO and PEG8000 and different clones of HDV. In our work, HDV infection rate increases from 0.1% to about 30% in the infection model. I also examine the expression of HDV genotype I, II and IV in the infection model. Since this infection model is established, the relationship between host and HDV can be further examined and eventually, find an effective antiviral therapy. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T04:43:21Z (GMT). No. of bitstreams: 1 ntu-107-R05445129-1.pdf: 4167416 bytes, checksum: 67b80dcbbfaf516bf5838bd81f191f4e (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 中文摘要...........................................................................................................................6
ABSTRACT.......................................................................................................................8 LIST OF ABBREVIATIONS..........................................................................................10 CHAPTER 1 INTRODUCTION 1.1 Clinical significance of HDV.............................................................................11 1.2 History of HDV..................................................................................................11 1.3 Virion structure of HDV.....................................................................................11 1.4 HDV life cycle 1.4.1 Attachment and entry................................................................................12 1.4.2 Transcription and translation....................................................................12 1.4.3 Replication and RNA species...................................................................13 1.4.4 Assembly and release................................................................................14 1.5 HDV cell infection model 1.5.1 Primary Human Hepatocyte (PHH) .......................................................14 1.5.2 HepaRG Cell Line..................................................................................15 1.5.3 hNTCP-Overexpressing Hepatoma Cell Lines.......................................15 1.6 Optimization of HDV infection system in hNTCP-overexpressing cell lines 1.6.1 Enhancement of HBV/HDV infection with PEG8000 and DMSO treatment..................................................................................................................16 1.6.2 Enhancement of HBV/HDV infection by suspension infection.....................16 1.7 Different HDV Genotypes 1.7.1 Clinical outcome of HDV genotypes..............................................................17 1.7.2 Expression of HDV genotypes in DNA transfection model...........................17 1.8 Hypothesis.........................................................................................................18 CHAPTER 2 MATERIALS AND METHODS 2.1 plasmid constructs.............................................................................................19 2.2 cell culture and cell lines...................................................................................22 2.3 HDV preparation and quantification.................................................................24 2.4 Infection.............................................................................................................26 2.5 Immunofluorescence assay................................................................................27 2.6 Western blotting.................................................................................................28 2.7 Northern blotting...............................................................................................30 2.8 Detection of HBsAg titer in supernatant...........................................................31 CHAPTER 3 RESULTS 3.1 Enhancement of HDV infectivity by infecting under suspension cell condition and DMSO treatment...............................................................................................32 3.2 Both HepG2-hNTCP-C4 cell line and HuH7-hNTCP-D8 cell line were susceptible to HDV infection...................................................................................33 3.3 Enhancement of HDV infection rate by 219 T to C point mutation..................34 3.4 2.0% DMSO treatment significantly increased the infection rate of HDV.........................................................................................................................36 3.5 Time course of cell infection model..................................................................37 3.6 Production of different HDV genotype virions.................................................38 3.7 Examination of different HDV genotypes in cell infection model....................40 CHAPTER 4 DISCUSSION...........................................................................................42 CHAPTER 5 CONCLUDING REMARKS....................................................................47 CHAPTER 6 FIGURES Figure 1 Enhancement of HDV infectivity by infecting under suspension cell condition and DMSO treatment...............................................................................48 Figure 2 Both HepG2-hNTCP-C4 cell line and HuH7-hNTCP-D8 cell line were susceptible to HDV infection...................................................................................51 Figure 3 Enhancement of HDV infection rate by 219 T to C point mutation...................................................................................................................53 Figure 4 2.0% DMSO treatment significantly increased the infection rate of HDV.........................................................................................................................60 Figure 5 Time course of cell infection model..........................................................67 Figure 6 Production of different HDV genotype virions.........................................73 Figure 7 Examination of different HDV genotype in cell infection model.............76 Supplementary data.................................................................................................80 APPENDIX.....................................................................................................................81 REFERENCES................................................................................................................89 | |
| dc.language.iso | en | |
| dc.subject | D型肝炎病毒 | zh_TW |
| dc.subject | 鈉離子牛磺膽酸共運轉蛋白 | zh_TW |
| dc.subject | 細胞感染模式 | zh_TW |
| dc.subject | D型肝炎病毒基因型 | zh_TW |
| dc.subject | 細胞懸浮感染 | zh_TW |
| dc.subject | 二甲基亞? | zh_TW |
| dc.subject | Hepatitis Delta Virus | en |
| dc.subject | sodium-taurocholate cotransporting polypeptide (NTCP) | en |
| dc.subject | cell infection model | en |
| dc.subject | HDV genotypes | en |
| dc.subject | suspension infection | en |
| dc.subject | Dimethyl sulfoxide (DMSO) | en |
| dc.title | 將D型肝炎病毒的感染模型最佳化並分析不同基因型的表現 | zh_TW |
| dc.title | Optimization of Cell Infection Model for Hepatitis Delta Virus (HDV) in hNTCP-overexpressing Hepatoma Cell Lines and Analysis of HDV Genotypes | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 葉秀慧(Shiou-Hwei Yeh),趙玫(Mei Chao) | |
| dc.subject.keyword | D型肝炎病毒,鈉離子牛磺膽酸共運轉蛋白,細胞感染模式,D型肝炎病毒基因型,細胞懸浮感染,二甲基亞?, | zh_TW |
| dc.subject.keyword | Hepatitis Delta Virus,sodium-taurocholate cotransporting polypeptide (NTCP),cell infection model,HDV genotypes,suspension infection,Dimethyl sulfoxide (DMSO), | en |
| dc.relation.page | 94 | |
| dc.identifier.doi | 10.6342/NTU201800799 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-08-03 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
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