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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 黃麗華 | |
| dc.contributor.author | Ya-Hui Tsai | en |
| dc.contributor.author | 蔡雅慧 | zh_TW |
| dc.date.accessioned | 2021-06-15T00:29:01Z | - |
| dc.date.available | 2014-02-17 | |
| dc.date.copyright | 2009-02-17 | |
| dc.date.issued | 2009 | |
| dc.date.submitted | 2009-01-20 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/41724 | - |
| dc.description.abstract | C型肝炎是全球性的重要肝臟疾病，並且是造成肝硬化及肝癌的主要病因之一。而目前所使用的干擾素(Interferon)及ribavirin合併療法對於HCV患者並無法達到令人滿意的治療效果。臨床觀察發現患者的治癒率會隨著其感染不同基因型的病毒而有很大的差異，感染基因型2的病人治癒率會顯著高於基因型1的病人。由於C型肝炎病毒的非結構蛋白NS5A被認為是C型肝炎病毒拮抗IFN效果的重要因子之一，我們針對NS5A所具有的IFN拮抗性深入探討，並研究NS5A是否為造成不同基因型HCV在治療反應上互異的可能原因。在第一部分的實驗中，我們證實了NS5A的確具有抑制IFN功能的作用，也找出NS5A中的ISDR區域、V3區域及C端區域對於NS5A所具有的IFN拮抗性最為重要。我們並收集了共十五名分別感染基因型1b及2a的HCV患者樣本，比較兩基因型來源的NS5A蛋白質對IFN的抑制效果，結果發現來自基因型1b的NS5A蛋白質確實會比來自基因型2a的NS5A蛋白質具有更強大的IFN拮抗效果。若將不同基因型的NS5A換入HCV replicon中，也同樣的可以發現帶有基因型1b的NS5A蛋白的replicon會對於IFN的處理具有較強的抵抗性。我們並分析出兩基因型之間在V3區域與C端區域的序列互換會左右NS5A蛋白質對IFN的抑制效果強弱。在第二部份的實驗中我們針對NS5A 能夠抑制IFN下游基因表現的機制進行探討。我們初步排除了NS5A對於JAK-STAT等多個參與IFN下游訊息傳導路徑的影響，因此希望尋找其他可能調控IFN下游基因表現且又被NS5A抑制的未知分子。我們利用TAP (tandem affinity purification)方法找到NS5A會與細胞中的heat shock protein 70-1 (Hsp70-1)結合。深入研究後發現在細胞中過度表現Hsp70-1能夠將IFN所引發的ISRE promoter活化作用增強至兩倍之多，而若將細胞中的Hsp70-1表現量以siRNA方法減少，則會發現IFN所引發的ISRE promoter活化作用降低了四分之一，由此可知Hsp70-1在細胞中對於IFN下游基因表現是具有正向調控的效果。如果將Hsp70-1與不同劑量的NS5A同時在細胞中表現時，NS5A會隨著劑量增高而逐漸把Hsp70-1對IFN引發ISRE活化所具有的正向增強效果給抑制抵銷掉。總結以上的實驗結果，不同基因型來源的NS5A所具有不同能力的IFN拮抗性或許可以用來部份說明不同基因型的HCV對IFN治療反應的差異；而NS5A與細胞內Hsp70-1的結合及抑制其對IFN正向調控的作用則可能是NS5A影響IFN功能的機制之一。 | zh_TW |
| dc.description.abstract | Chronic hepatitis C infection is a global health burden as being the leading cause of liver cirrhosis and hepatocellular carcinoma. Currently, interferon (IFN) therapy, in combination with ribavirin, has been the most widely used treatment for hepatitis C virus (HCV) infection. It has a sustained response rate of about 75~80% for patients infected with HCV genotype 2, but only about 35~45% for those infected with HCV genotype 1. Since the non-structural 5A protein (NS5A) of HCV had been suggested as one of the viral determinants of IFN resistance, the present study investigated the anti-IFN mechanism of NS5A and whether NS5A of HCV genotypes 1 and 2 (1b-NS5A and 2a-NS5A, respectively) exerted differential counteractive effects against IFN treatment. First, we validated the IFN antagonism of NS5A and identified the interferon sensitivity-determining region/protein kinase R-binding domain (ISDR/ PKR-BD), the V3 domain, and the C-terminus region as the domains required for its anti-IFN activity. In the comparison between genotypes, it was found that 1b-NS5As exerted more profound inhibitory effects on IFN activity than 2a-NS5As. The replication of the 2a-NS5A-containing replicons was more sensitive to IFN treatment than that of the 1b-NS5A-containing replicons. By domain swapping, we found the V3 and the C-terminus regions were responsible for the differential anti-IFN effects between genotypes. Next, we focused on investigating the underlying mechanism by which NS5A inhibits the IFN-induced expression of interferon-stimulated genes (ISGs). By examining the JAK-STAT signaling and other alternative pathways that regulate IFN-induced transcription, we found no effect of NS5A on these signaling pathways. Thus we aimed at discovering other cellular molecules that involve in IFN-induced ISRE activation and that is targeted by NS5A. We used tandem affinity purification (TAP) to find NS5A-interacting cellular factors. As a result, heat shock protein 70-1 (Hsp70-1) was identified by LC-MS/MS analysis. The interaction between NS5A and Hsp70-1 was confirmed by co-immunoprecipitation assay in vivo. The exploration on the role of Hsp70-1 in IFN-induced ISRE activation revealed that overexpression of Hsp70-1 in 293T cells resulted in a 114% increase of IFN-induced ISRE activation, and knockdown of Hsp70-1 resulted in a 25% decrease. Furthermore, the positive regulation of Hsp70-1 on IFN-induced ISRE activation was offset by NS5A in a dose-dependent manner. These observations demonstrated that Hsp70-1 functions as a positive regulator in IFN-induced signaling and there are counteractive effects between Hsp70-1 and NS5A. In conclusion, that 1b-NS5As exert higher magnitudes of IFN antagonism than do 2a-NS5As may partly explain the genotype-linked differences in the response of HCV to IFN treatment and that NS5A interacts with and inhibits Hsp70-1 provides a possible mechanism by which NS5A utilizes to disturb IFN-induced ISRE activation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T00:29:01Z (GMT). No. of bitstreams: 1 ntu-98-F90445104-1.pdf: 3590574 bytes, checksum: 350e88067ad4b72774473628a5ab9ca6 (MD5) Previous issue date: 2009 | en |
| dc.description.tableofcontents | 中文摘要 i
Abstract iii Table of Contents v Chapter 1 Introduction 1 1.1 Hepatitis C Virus 2 1.1.1 HCV genome and viral proteins 2 1.1.2 HCV Replication 4 1.1.3 Treatment strategy and virologic response rate 5 1.1.4 HCV infection in Taiwan 6 1.2 Type I Interferon 7 1.2.1 Induction of Type I IFN production 7 1.2.2 IFN Signaling pathway 9 1.2.3 Alternative pathways and accessory components of type I IFN signaling 10 1.2.4 Antiviral activities and virus evasion 14 1.3 Interaction between Hepatitis C Virus and Type I Interferon System 15 1.3.1 HCV as a trigger of IFN anti-viral activity 15 1.3.2 HCV proteins with anti-IFN activity 16 1.4 Hepatitis C Virus NS5A Protein and its Anti-Interferon Activity 16 1.4.1 Protein structure and function of NS5A protein 17 1.4.2 The ISDR, the PKR-BD, and inhibition of PKR 18 1.4.3 The V3 region 20 1.4.4 Inhibition of 2’, 5’-OAS pathway 20 1.4.5 Induction of IL-8 expression 21 1.5 Heat Shock Protein 70 Family 22 1.5.1 Cellular functions of Hsp70s 22 1.5.2 Structure of Hsp70s 22 1.5.3 Molecular mechanism of the Hsp70 chaperons 23 1.5.4 Hsp70-1 24 1.6 Specific Aims of this Study 25 1.6.1 To investigate the IFN antagonism of NS5A proteins from genotypes 1b and 2a 25 1.6.2 To explore the possible mechanisms which NS5A employs to disturb IFN-induced ISRE activation 25 Chapter 2 Materials and Methods 27 2.1 Cell Lines 28 2.2 Constructs 28 2.3 Western Blotting and Antibodies 30 2.4 Silver Staining 32 2.5 Viruses 33 2.6 Plaque Assay 33 2.7 Trans-Rescue Assay 34 2.8 ISRE-Luc Reporter Assay 35 2.9 Quantitative Real-Time PCR Analysis of ISGs 35 2.10 HCV Replicon RNA Transfection and Replication Analysis 36 2.11 Chromatin Immunoprecipitation 37 2.12 TAP Purification of NS5A-Interacting Cellular Proteins 39 2.13 Co-Immunoprecipitation 40 2.14 Knockdown of Hsp70-1 and PKR by siRNA 40 Chapter 3 Results 42 3.1 HCV NS5A inhibits IFN activity with a genotype-related manner 43 3.1.1 HCV NS5A inhibits IFN-induced ISRE promoter activation and IFN-mediated anti-VSV activity 43 3.1.2 The ISDR/PKR-BD, the V3 domain, and the C-terminus region are required for the anti-IFN activity of NS5A 45 3.1.3 1b-NS5As and 2a-NS5As display differential inhibitory effects on the IFN-induced signaling, anti-viral activity, and transcription of ISGs 46 3.1.4 The HCV subgenomic and genomic replicons harboring 1b-NS5A or 2a-NS5A display differential IFN responses 48 3.1.5 HCV 1b-NS5A sequences are distinct from 2a-NS5A sequences in three major regions 49 3.1.6 The V3 and the C-terminus regions are responsible for the differential anti-IFN effects of 1b-NS5As and 2a-NS5As 51 3.2 Mechanistic investigation of the IFN antagonism of NS5A 52 3.2.1 IFN-induced transduction of JAK-STAT signaling and the interaction of ISGF3 complex with ISRE were not affected by NS5A 53 3.2.2 PKR is not required for ISRE-Luc activation in our assay model 54 3.2.3 NS5A does not inhibit IFN-induced activation of p38 55 3.2.4 NS5A does not affect the phosphorylation on Ser727 of STAT1 57 3.2.5 NS5A does not induce IL-8 expression in our assay system 57 3.3 The interaction of NS5A with Hsp70-1 58 3.3.1 Hsp70-1 is identified as a NS5A-interacting cellular protein 58 3.3.2 NS5A interacts with Hsp70-1 in vivo 59 3.3.3 The domains required for the NS5A-Hsp70-1 interaction 60 3.3.4 Hsp70-1 has a positive regulative role on IFN-induced ISRE activation 61 3.3.5 The counteractive effect between NS5A and Hsp70-1 62 3.3.6 1b- and 2a-NS5As show no genotypic difference in the interaction with Hsp70-1 63 Chapter 4 Discussion and Concluding Remarks 66 4.1 Summary 67 4.2 The genotypic difference of NS5A 68 4.3 The mechanism of the IFN antagonism of NS5A 71 4.4 Interaction between NS5A and Hsp70-1 74 4.5 Future directions and concluding remarks 77 Chapter 5 Figures & Tables 79 Figure 1. Inhibition of IFN-induced ISRE-Luc expression and anti-VSV activity by HCV NS5A. 80 Figure 2. The inhibition of IFN activity by HCV NS5A is not a cell-type or virus-type specific effect. 81 Figure 3. The domains essential for the IFN antagonism of NS5A. 82 Figure 4. NS5A proteins from genotypes 1b and 2a exhibit differential inhibitory effects on IFN activity. 84 Figure 5. NS5A proteins from genotypes 1b and 2a exhibit differential inhibitory effects on IFN-induced expression of endogenous ISGs. 86 Figure 6. HCV replicons containing NS5A protein from genotypes 1b and 2a exhibit differential response to IFN treatment. 87 Figure 7. Amino acid sequence alignment between 1b-NS5As and 2a-NS5As 88 Figure 8. Domain swapping was performed to determine the regions responsible for the differential anti-IFN activity between 1b-NS5As and 2a-NS5As. 90 Figure 9. Effects of NS5A on the interaction of ISGF3 complex with ISRE-containing promoters. 92 Figure 10. Verification of the role of PKR in IFN-induced ISRE activation. 93 Figure 11. Verification of the role of p38 in IFN-induced ISRE activation and the effect of NS5A on p38 phosphorylation. 94 Figure 12. Effect of NS5A on IFN-induced phosphorylation on STAT1 Ser721. 95 Figure 13. Effect of NS5A on the expression level of IL-8 RNA. 96 Figure 14. TAP purification of NS5A-interacting cellular proteins. 97 Figure 15. The LC-MS/MS report revealed a NS5A-interacting protein as Hsp70-1. 98 Figure 16. Confirmation of the interaction between NS5A and Hsp70-1. 99 Figure 17. The interacting domain within NS5A to bind Hsp70-1. 100 Figure 18. The interacting domain within Hsp70-1 to bind NS5A. 101 Figure 19. Hsp70-1 enhanced IFN-induced ISRE activation. 102 Figure 20. The functional interaction between NS5A and Hsp70-1. 103 Figure 21. The interaction between Hsp70-1 with 1b-NS5As and 2a-NS5As. 104 Figure 22. The effect of Hsp70-1 knockdown on the replication of HCV. 105 Table 1. The primers used for the generation of NS5A deletion mutants 106 Table 2. The primers used for real-time PCR quantification of gene expression 107 Table 3. The primers used for real-time quantification of HCV replicon RNA 108 Table 4. The primers used for PCR amplification of ISG promoters in ChIP assay 109 Table 5. Primers used for the cloning of wild-type and mutants of Hsp70-1 110 Chapter 6 References 111 Appendix 127 | |
| dc.language.iso | en | |
| dc.subject | C型肝炎病毒 | zh_TW |
| dc.subject | 干擾素拮抗作用 | zh_TW |
| dc.subject | 基因型 | zh_TW |
| dc.subject | 非結構蛋白5A | zh_TW |
| dc.subject | IFN antagonism | en |
| dc.subject | Hsp70-1 | en |
| dc.subject | Genotype | en |
| dc.subject | NS5A | en |
| dc.subject | Hepatitis C virus | en |
| dc.title | C型肝炎病毒非結構蛋白5A對甲型干擾素具有拮抗作用之機制探討 | zh_TW |
| dc.title | Mechanistic Investigation of the IFN-alpha Antagonism of Hepatitis C Virus Non-Structural Protein 5A | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 97-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 陳培哲,陳美如,董馨蓮,李建國,林宜玲 | |
| dc.subject.keyword | C型肝炎病毒,非結構蛋白5A,基因型,干擾素拮抗作用, | zh_TW |
| dc.subject.keyword | Hepatitis C virus,NS5A,Genotype,IFN antagonism,Hsp70-1, | en |
| dc.relation.page | 128 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2009-01-20 | |
| 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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