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研究生:郭澤民
研究生(外文):Tzer-Min Kuo
論文名稱:第六介白質抑制B型肝炎病毒複製之研究
論文名稱(外文):HBV replication is significantly reduced by IL-6
指導教授:張仲明
指導教授(外文):Chungming Chang
學位類別:博士
校院名稱:國立陽明大學
系所名稱:微生物及免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:112
中文關鍵詞:細胞激素B型肝炎病毒複製帶有基因體的核心顆粒抗病毒作用
外文關鍵詞:cytokinesHBV replicationgenome-containing nucleocapsidsantiviral effect
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慢性B型肝炎已知是造成肝硬化與肝癌的高危險因子,人類極為嚴重的病毒感染疾病之一。B型肝炎病毒感染所產生的肝臟疾病,其致病過程牽涉到病毒複製與對抗病毒所誘發的免疫反應等複雜機轉。為了有效的控制疾病,了解慢性B型肝炎致病過程中病毒複製的調控是相當重要的。藉由體外細胞轉染與基因轉殖小鼠為實驗模型,目前的研究已經證實了促發炎性細胞激素可以在不造成細胞病變的情形下,抑制B型肝炎病毒的複製。

第六介白質為一多效型的細胞激素,對包括肝細胞在內之標的細胞在生物反應的調控上具有極關鍵的作用。已知在慢性B型肝炎、肝硬化與肝癌患者血清中第六介白質濃度會有明顯的上升。相較於其他的細胞激素,第六介白質更是一個在臨床上肝臟疾病進展的良好指標。在本篇論文中,我們研究第六介白質對B型肝炎病毒複製的抑制活性。藉由會持續產生B型肝炎病毒顆粒的細胞株進行實驗,我們發現,第六介白質可以有效的抑制B型肝炎病毒複製並且阻止病毒共價連鎖閉合環型去氧核醣核酸在細胞核的堆積。我們也證明第六介白質對B型肝炎病毒複製的抑制作用主要是透過較緩和的減少病毒的轉錄產物與核心蛋白的表現,以及顯著的降低帶有病毒基因體的病毒核心顆粒總量。針對第六介白質對病毒核心顆粒穩定性的測試,我們認為第六介白質對病毒核心顆粒總量的抑制是透過阻止病毒核心顆粒的形成而非影響病毒核心顆粒的穩定性,這樣的機轉與干擾素對B型肝炎病毒的抑制作用是相似的。此外,我們證明不論是干擾素-α或β以及干擾素-γ均沒有參與第六介白質對病毒複製的抑制作用。更進一步的實驗結果顯示活化PI3K-Akt 訊息傳遞路徑參與第六介白質對病毒複製的抑制作用。綜合以上的觀察,我們的研究結果說明了第六介白質在減少病毒複製的重要性,並且在對抗病毒的免疫反應中與其他促發炎性細胞激素協同抑制B型肝炎病毒的感染。
Chronic hepatitis B(CHB) is a well-known high risk factor for cirrhosis and hepatocellular carcinoma and still remains one of the most serious viral infections in humans. The pathogenesis of hepatitis B virus(HBV)-induced liver diseases involves complicated mechanisms revolving around viral replication and immune responses against HBV infection. To effectively control this disease, it will be important to understand the regulatory mechanisms of viral replication during the progression of CHB. It is well documented that HBV replication can be suppressed noncytopathically by several proinflammatory cytokines in both cell culture system and transgenic mouse model.

Interleukin-6(IL-6) is a pleiotropic cytokine with pivotal functions in the regulation of the biological responses of several target cells including hepatocytes. The level of serum are elevated in patients with chronic hepatitis B, cirrhosis and hepatocellular carcinoma and represent the best marker of HBV-related clinical progression as compared with several other cytokines. In this thesis, we investigated the inhibitory effect of IL-6 on HBV replication. By using a virion-producing cell line (1.3ES2), we found that IL-6 was able to effectively inhibit HBV replication and prevent the accumulation of HBV covalently closed circular DNA (cccDNA). We also demonstrated that the suppression of HBV replication by IL-6 requires concurrently a moderate reduction of viral transcripts/core proteins and a marked decrease in viral genome-containing nucleocapsids. Studies on the stability of existing viral capsids suggest that the IL-6 effect on the reduction of genome-containing nucleocapsids is mediated through the prevention of the formation of genome-containing nucleocapsids, which is similar to the effect of interferons. However, IFN-α/β and IFN-γ did not participate in the IL-6-induced suppression of HBV replication. Further studies also revealed that the activation of the PI3K-Akt signaling pathway was involved in the suppressive effect of IL-6. Taken together, our data suggest that IL-6 may play an important role in restricting the viral replication and cooperate with other inflammatory cytokines to control viral infection.
中文摘要………………………………………………………………………………1
英文摘要………………………………………………………………………………2
壹、緒論………………………………………………………………………………4
第一部份:B型肝炎病毒生物學與相關研究之介紹………………………………4
一、B型肝炎病毒構造與基因體……………………………………………………4
二、B型肝炎病毒基因體的複製與生活史…………………………………………8
第二部份:細胞激素在B型肝炎病毒免疫反應之角色……………………………9
一、B型肝炎病毒所誘發的免疫反應………………………………………………9
二、細胞激素對B型肝炎病毒複製抑制之研究……………………………………10
三、第六介白質與其訊息傳導路徑…………………………………………………11
四、第六介白質與肝臟、B型肝炎病毒的交互作用………………………………13
第三部份:論文研究源起……………………………………………………………15
貳、材料與方法…………………………………………………………………… 16
一、細胞培養…………………………………………………………………………16
二、質體的構築………………………………………………………………………16
三、質體的轉染………………………………………………………………………17
四、全細胞的病毒DNA的製備與南方墨點分析法………………………………17
五、病毒cccDNA的製備:Hirt萃取法………………………………………………18
六、全細胞RNA(核醣核酸)的製備…………………………………………………19
七、北方墨點分析法…………………………………………………………………19
八、反轉錄-聚合酶鏈鎖反應………………………………………………………19
九、細胞培養液中病毒核酸的偵測…………………………………………………20
十、西方墨點分析法(Western blot analysis) …………………………………………21
十一、酵素免疫分析法(Enzyme-Linked Immunosorbent Assay, ELISA)…………22
十二、免疫沉澱法(Immunoprecipication, IP)………………………………………22
十三、Particle blot 分析法……………………………………………………………23
十四、干擾素中和試驗………………………………………………………………24
十五、細胞內病毒核心顆粒的穩定性分析…………………………………………24
參、結果………………………………………………………………………………25
一、第六介白質可以抑制B型肝炎病毒的複製……………………………………25
二、第六介白質透過降低細胞內帶有病毒基因體核心顆粒總量與病毒RNA或核心蛋白表現量抑制B型肝炎病毒的複製…………………………………………26
三、第六介白質並不破壞B型肝炎病毒核心顆粒…………………………………27
四、第六介白質的抗病毒作用並非經由干擾素的誘發而達成……………………28
五、第六介白質可以阻止病毒cccDNA的形成……………………………………29
六、第六介白質經由JAK-PI3K訊息傳遞路徑抑制B型肝炎病毒的複製………29
肆、討論………………………………………………………………………………32
一、第六介白質在B型肝炎病毒所誘發之免疫反應所扮演的角色………………32
二、第六介白質與其他具抑制B型肝炎病毒複製之細胞激素比較………………34
三、第六介白質抑制B型肝炎病毒複製之機轉……………………………………34
四、抑制B型肝炎病毒複製的訊息傳遞路徑………………………………………36
附錄:基因型A與D之B型肝炎病毒剪接RNA的選殖與分析
Cloning and characterization of spliced RNA generated form genotype A and D hepatitis B virus
中文摘要……………………………………………………………………………38
英文摘要……………………………………………………………………………39
壹、緒論………………………………………………………………………………40
一、 B型肝炎病毒的分類與其基因型……………………………………………40
二、 B型肝炎病毒剪接RNA的研究發現…………………………………………41
三、 B型肝炎病毒剪接RNA所表現的蛋白………………………………………42
四、論文研究源起……………………………………………………………………44
貳、材料與方法………………………………………………………………………45
一、細胞培養…………………………………………………………………………45
二、質體的構築………………………………………………………………………45
三、質體的轉染………………………………………………………………………46
四、全細胞RNA(核醣核酸)的製備…………………………………………………46
五、反轉錄-聚合酶鏈鎖反應………………………………………………………47
六、TA Clonning………………………………………………………………………47
七、選殖之B型肝炎病毒剪接DNA結構分析……………………………………48
八、北方墨點分析法…………………………………………………………………48
參、結果………………………………………………………………………………49
ㄧ、B型肝炎病毒病毒剪接RNA的偵測與結構分析……………………………49
二、基因型D與基因型A 之B型肝炎病毒剪接RNA種類的分布………………50
三、基因型D與基因型A中保留的B型肝炎病毒剪接位使用頻率………………51
四、B型肝炎病毒剪接RNA在全部B型肝炎病毒RNA所佔比例分析…………52
肆、討論………………………………………………………………………………54
一、剪接RNA的種類分佈…………………………………………………………54
二、剪接位的使用……………………………………………………………………55
三、病毒剪接RNA在全部B型肝炎病毒RNA中所佔比例………………………56
參考文獻……………………………………………………………………………58
圖一〜二十四………………………………………………………………………73
表一〜三……………………………………………………………………………97
由本論文結果所發表之相關文獻…………………………………………………100
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