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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/66063完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 黃麗華(Lih-Hwa Hwang) | |
| dc.contributor.author | Shih-Hui Chen | en |
| dc.contributor.author | 陳詩蕙 | zh_TW |
| dc.date.accessioned | 2021-06-17T00:20:35Z | - |
| dc.date.available | 2017-09-19 | |
| dc.date.copyright | 2012-09-19 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-06-24 | |
| dc.identifier.citation | 1. Wright TL, Lau JY (1993) Clinical aspects of hepatitis B virus infection. Lancet 342: 1340-1344.
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Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, et al. (2007) Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 357: 2576-2588. 168. Yao H, Ng SS, Tucker WO, Tsang YK, Man K, et al. (2009) The gene transfection efficiency of a folate-PEI600-cyclodextrin nanopolymer. Biomaterials 30: 5793-5803. 169. Penna A, Del Prete G, Cavalli A, Bertoletti A, D'Elios MM, et al. (1997) Predominant T-helper 1 cytokine profile of hepatitis B virus nucleocapsid-specific T cells in acute self-limited hepatitis B. Hepatology 25: 1022-1027. 170. Ferrari C, Penna A, Bertoletti A, Valli A, Antoni AD, et al. (1990) Cellular immune response to hepatitis B virus-encoded antigens in acute and chronic hepatitis B virus infection. J Immunol 145: 3442-3449. 171. Kamatani Y, Wattanapokayakit S, Ochi H, Kawaguchi T, Takahashi A, et al. (2009) A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/66063 | - |
| dc.description.abstract | 研究B型肝炎病毒（hepatitis B virus，HBV）造成慢性帶原的機制一直是個很有挑戰性的問題。由於缺乏適合之HBV長期帶原的動物模式，因此感染病毒之後如何轉變成慢性帶原的成因仍然不清楚。在本研究中，我們利用高壓流體注射法（hydrodynamic injection）將病毒replicon DNA打到BALB/c、C57BL/6、FVB/N三種不同品系的小鼠身上，該replicon DNA便能在肝臟複製並產生病毒顆粒。在BALB/c、C57BL/6小鼠可以很快的將病毒清掉，然而我們發現在FVB/N小鼠身上HBV可以帶原長達五十週之久。以流式細胞儀與反轉錄定量PCR分析小鼠的肝臟發現FVB/N小鼠的毒殺性T細胞（cytotoxic T lymphocyte，CTL）、血清轉氨酶（alanine aminotransferase，ALT）、丙型干擾素（interferon-γ，IFN-γ）、甲型腫瘤壞死因子（tumor necrosis factor-α，TNF-α）、第九、第十號趨化激素（CXCL9、CXCL10）比另外兩種品系小鼠產生得少，反映出肝臟發炎程度與病毒清除效率的相關性。利用突變分析進一步證明若將HBV表面抗原的第214個胺基酸由Asparagine轉變成Serine則會使原本能夠帶原的clone被清除掉，此現象亦伴隨著活化的CTL、IFN-γ、CXCL9、CXCL10的增加。此動物模式亦適合用來評估抗HBV藥物的療效。在帶原小鼠增加CXCL9、CXCL10與補體5a（Complement 5a，C5a）的表現能夠促進病毒的清除。本研究的結果指出，不同的宿主遺傳背景與病毒序列會影響對抗HBV的免疫反應。免疫系統或發炎反應不恰當的活化可能導致HBV的慢性帶原。 | zh_TW |
| dc.description.abstract | The mechanism underlying the chronicity of hepatitis B virus (HBV) infection has long eluded researchers. The mechanism has remained unclear largely due to the lack of an animal model that can support persistent HBV replication and allow for the investigation of the relevant immune responses. In this study, we used hydrodynamic injection to introduce HBV replicon DNA into the livers of three different mouse strains, BALB/c, C57BL/6, and FVB/N. Interestingly, we found that an HBV clone persistently replicated in the livers of FVB/N mice for up to 50 weeks but was rapidly cleared from the livers of BALB/c and C57BL/6 mice. Flow cytometric analysis and quantitative reverse transcription PCR analysis of the mouse livers indicated that after DNA injection, FVB/N mice had few intrahepatic activated cytotoxic T lymphocytes (CTLs) and produced low levels of alanine aminotransferase, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and the CXCL9 and CXCL10 chemokines. These responses were in sharp contrast to those observed in BALB/c and C57BL/6 mice, reflecting a strong correlation between the degree of liver inflammation and viral clearance. Mutational analysis further demonstrated that a change from Asn-214 to Ser-214 in the HBV surface antigen permitted the clearance of the persistent HBV clone in FVB/N mice, and the response was accompanied by increased levels of activated CTLs and upregulated liver expression of IFN-γ, CXCL9, and CXCL10. The model was demonstrated to be useful for the in vivo evaluation of the efficacies of various anti-HBV drugs. Supplementary expression of CXCL9, CXCL10 and C5a in the carrier mice enhanced the clearance of the chronic infection. These results indicate that the heterogeneity of the host factors and viral sequences may influence the immune responses against HBV. An inadequate activation of immune or inflammatory responses can lead to persistent HBV replication in vivo. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T00:20:35Z (GMT). No. of bitstreams: 1 ntu-101-D93445002-1.pdf: 3723962 bytes, checksum: ee14f2c282fc024b09ac29836186e5f6 (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | 致謝.......................................................i
中文摘要...................................................ii Abstract.................................................iii Table of Contents..........................................v Chapter 1 Introduction.....................................1 1.1 Hepatitis B virus......................................2 1.1.1 The HBV genome and viral proteins....................2 1.1.2 The replication cycle of HBV.........................3 1.1.3 The natural history of HBV infection.................4 1.1.3.1 Transient infection................................4 1.1.3.2 Persistent infection...............................5 1.2 The immune responses against HBV infection.............7 1.2.1 Innate defense mechanisms............................7 1.2.2 The adaptive immune response.........................9 1.2.2.1 The role of CTLs in HBV pathogenesis..............10 1.2.2.2 Mechanisms of CTL-induced viral clearance.........11 1.2.2.3 T-helper cells....................................12 1.3 Viral factors that regulate the immune response.......12 1.3.1 HBeAg...............................................12 1.3.2 HBsAg...............................................13 1.3.3 HBV X protein.......................................13 1.3.4 HBV polymerase......................................13 1.3.5 Mutational escape...................................14 1.4 Animal models of HBV infection........................14 1.4.1 Chimpanzee..........................................14 1.4.2 Woodchuck...........................................15 1.4.3 Duck................................................15 1.4.4 Tupaia..............................................16 1.4.5 Chimeric mice.......................................17 1.4.6 Transgenic mice.....................................17 1.4.7 Transfection of mice................................18 1.4.7.1 HBV in an adenoviral vector.......................18 1.4.7.2 HBV in an adeno-associated viral (AAV) vector.....19 1.4.7.3 Hydrodynamic injection of HBV DNA.................19 1.5 Specific aim of this study............................20 Chapter 2 Materials and Methods...........................22 2.1 Ethics statement......................................23 2.2 Plasmid construction..................................23 2.3 Animal experiments....................................25 2.4 Detection of HBeAg and ALT in the Serum...............26 2.5 Southern blot analysis of HBV DNA in the livers.......26 2.6 Immunohistochemistry..................................26 2.7 Isolation of intrahepatic lymphocytes.................26 2.8 Flow cytometric analysis..............................27 2.9 qRT-PCR analysis of cytokine and chemokine gene expression................................................27 2.10 IFN-γ ELISPOT assay..................................28 2.11 Transfection of HBV DNA in tissue culture cells......29 2.12 HBV RNA analysis.....................................29 2.13 Western blot analysis................................30 2.14 Luciferase assay.....................................30 2.15 DNA Immunization.....................................30 2.16 Detection of HBV viral titer.........................31 2.17 Statistical analysis.................................31 Chapter 3 Results.........................................32 3.1 The host genetic background influences HBV persistence in vivo...................................................33 3.2 HBeAg clearance correlates with elevated levels of ALT, increased numbers of activated CTLs, and severity of liver inflammation..............................................34 3.3 Complement 5 deficiency and the H-2q MHC haplotype may contribute to the HBV persistence observed in FVB/N mice..36 3.4 HBV viral sequences affect HBV persistence in FVB/N mice......................................................37 3.5 Clearance of the mutant HBV clone B6.2S correlates with induction of liver inflammation...........................38 3.6 A CTL epitope restricted to H-2q was detected behind the N214S mutation in the large HBsAg.........................39 3.7 Carrier mice can serve as a good animal model for the in vivo screening of anti-HBV drugs..........................41 3.8 Chemokines have the potential to hasten viral clearance in the HBV carrier FVB/N mouse model......................42 3.9 Hydrodynamic injection of CXCL10 DNA promotes the recruitment of inflammatory cells in carrier FVB/N mice, but not in naive mice.........................................43 3.10 Hydrodynamic injection of chemokine DNA causes necroinflammation in the livers of HBV carrier mice.......44 Chapter 4 Discussion......................................45 4.1 HBV persistence in the nontransgenic FVB/N mouse model is due to three essential factors, the genetic background of the host, the appropriate viral sequence, and the environmental factors.....................................46 4.2 HBV carrier FVB/N mice as a model for anti-viral drug screening.................................................49 4.3 CXCL9 and CXCL10 amplify the inflammatory response and hasten the clearance of HBV...............................50 4.4 Conclusions and future directions.....................51 Chapter 5 Figures and Tables..............................53 Figure 1. The pGEM4Z/HBV1.3 replicon plasmid..............54 Figure 2. The pORF/L-HBs expression plasmid...............55 Figure 3. Schematic diagrams of the chemokine expression vectors...................................................56 Figure 4. Long-term follow up of serum HBeAg in the animals injected with the pHBV1.3-B6 replicon DNA…................57 Figure 5. The duration of HBV replicative intermediates present in the livers of the replicon DNA-injected animals...................................................58 Figure 6. The kinetics of ALT elevation, infiltration of activated CTLs, and the expression of cytokines and chemokines in different mouse strains after DNA injection.................................................59 Figure 7. Flow cytometric analysis of the levels of activated CTLs in the livers of different mouse strains after DNA injection.......................................61 Figure 8. HBV specific CTL responses detected by IFN-γ ELISPOT assay.............................................62 Figure 9. Histological analysis of the livers from different mouse strains injected with HBV DNA.......................63 Figure 10. Long-term follow up of serum HBeAg in DBA/1 and DBA/2 mice injected with pHBV1.3-B6 DNA...................64 Figure 11. Different persistence rates of different HBV isolates..................................................65 Figure 12. The replication and gene expression efficiencies of different HBV isolates.................................66 Figure 13. Different persistence rates conferred by a single amino acid change in the HBV surface protein..............68 Figure 14. The levels of ALT, activated CTLs, and the liver expression of cytokines and chemokines in FVB/N mice following injection with pHBV1.3-B6.2 or -B6.2S DNA.......69 Figure 15. Histological analysis of the livers of FVB/N mice injected with pHBV1.3-B6.2 or -B6.2S replicon DNA.........71 Figure 16. No peptide-specific T cell response in FVB/N mice......................................................72 Figure 17. No T cell response specific to the Asn-214 region was observed in the FVB/N mice intramuscularly immunized with HBsAg-expressing DNA.................................73 Figure 18. HBsAg28-39 may be a CTL epitope of FVB/N mice..74 Figure 19. Anti-viral drug screening......................75 Figure 20. The HBV carrier FVB/N mice treated with chemokine expression vectors........................................76 Figure 21. Histological analysis of the livers of naive and carrier FVB/N mice injected with pGEM4Z or the chemokine expression vectors........................................77 Figure 22. Histological analysis of the livers of carrier FVB/N mice injected with chemokine expression DNAs........79 Figure 23. Clearance of HBV strongly correlates with the presence of intrahepatic CTLs and the severity of liver inflammation during viral infection.......................80 Table 1. The sequences of primers used for plasmid construction, site-directed mutagenesis, and real-time PCR analysis..................................................81 Table 2. Mutation sites of the amino acid residues in the six sub-clones compared to the B6 consensus sequence......82 Table 3. Peak levels of activated CTL and inflammatory cytokines.................................................83 Chapter 6 References......................................84 Appendix.................................................100 | |
| dc.language.iso | en | |
| dc.subject | 慢性帶原 | zh_TW |
| dc.subject | 宿主遺傳背景 | zh_TW |
| dc.subject | 高壓流體注射法 | zh_TW |
| dc.subject | B型肝炎病毒 | zh_TW |
| dc.subject | 病毒因子 | zh_TW |
| dc.subject | host genetic background | en |
| dc.subject | viral factor | en |
| dc.subject | persistency | en |
| dc.subject | hydrodynamic injection | en |
| dc.subject | Hepatitis B virus | en |
| dc.title | 於FVB/N小鼠建立B型肝炎病毒慢性帶原模式以研究宿主與病毒的影響因素 | zh_TW |
| dc.title | Persistent Hepatitis B Viral Replication in an FVB/N Mouse Model: Impact of Host and Viral Factors | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 高嘉宏(Jia-Horng Kao),陳培哲(Pei-Jer Chen),吳慧琳(Hui-Lin Wu),李建國(Chien-Kuo Lee),陶秘華(Mi-Hua Tao) | |
| dc.subject.keyword | B型肝炎病毒,高壓流體注射法,慢性帶原,病毒因子,宿主遺傳背景, | zh_TW |
| dc.subject.keyword | Hepatitis B virus,hydrodynamic injection,persistency,viral factor,host genetic background, | en |
| dc.relation.page | 103 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2012-06-25 | |
| 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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