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標題: | C型肝炎病毒基因型1b和2a非結構性蛋白質NS3/4A對細胞干擾素反應的抑制能力之比較 The comparison of different inhibitory effects of hepatitis C virus NS3/4A from genotypes 1b and 2a on cellular interferon responses |
作者: | Yung-Chi Huang 黃詠琪 |
指導教授: | 黃麗華 |
關鍵字: | C型肝炎病毒,干擾素,病毒基因型, Hepatitis C virus,interferon,HCV genotypes, |
出版年 : | 2007 |
學位: | 碩士 |
摘要: | C型肝炎病毒 (HCV)感染無論在台灣或是全球都是很重要的公共衛生課題。根據世界衛生組織的統計,全世界約有一億七千萬的人口為HCV帶原者,其中高達百分之八十的人在二十到三十年內會產生肝硬化,甚且發展成惡性肝細胞癌。目前最有效的治療藥物為長效型甲型干擾素結合抗病毒藥物ribavirin,然而,隨著病毒基因型的不同,治療成效約在50-80%不等。同時,感染後發展成慢性肝炎的機率以及所伴隨的肝臟疾病的嚴重程度在病毒基因型間也有所不同。本研究主要想澄清基因型1b和2a病毒 (台灣最普遍的兩種基因型)的NS3/4A對於細胞中干擾素的產生及治療作用是否有所不同,最後導致臨床上所觀察到的差異。我們從病人血清中分離出分屬基因型1b和2a各三個NS3/4A clones。首先,檢視其對於IFN-β啟動子驅使的冷光素酵素報導基因之活性的抑制及對MAVS的切割能力。並且,利用ISRE啟動子驅使的冷光素酵素報導基因之活性和trans-rescue測定,觀察NS3/4A對IFN-α下游訊息傳導抑制的能力。根據以上的分析結果,並未發現基因型1b和2a的NS3/4A有能力上的差異。因此,推測C型肝炎病毒中的NS3/4A對於不同基因型病毒感染的患者所表現出的臨床差異上,並未扮演關鍵性的角色。論文中的第二部分,我們試圖找出能加強細胞對干擾素負向調控的C型肝炎病毒蛋白質。根據初步的結果,發現在肝癌細胞中表現C型肝炎病毒的core會增加細胞中SOCS3 mRNA的量。另外,表現NS3/4A,,NS4B 和NS5A 則能使人類單核球細胞中抑制細胞抗病毒作用的細胞激素IL-8 與TNF-α的表現量增加。對於C型肝炎病毒如何負向調控細胞中干擾素的作用,並且增加對IFN-α治療的抵抗,則需更深入的研究。 Hepatitis C virus (HCV) is a major etiologic pathogen that infects 170 million people worldwide and causes chronic hepatitis, which often leads to liver cirrhosis, and hepatocellular carcinoma. The standard therapy for chronic HCV infection is a combination of PEG-IFN-α (pegylated-interferon-α) and ribavirin, which could eliminate HCV in 50-80% of the patients with chronic active hepatitis. However, the rate of successful elimination varies significantly with virus genotypes. Also, the rate of evolution to chronic hepatitis and the severity of liver disease are different among the patients infected by different HCV genotypes. Here, we attempted to clarify whether the different clinical outcomes in patients infected with HCV genotypes 1b and 2a, the two most prevalent genotypes in Taiwan, were due to the different inhibitory effects of the NS3/4A proteins on cellular IFN response. Three clones of each HCV genotype 1b or 2a were isolated from patients. We first compared the efficacies of these NS3/4A in interrupting the IFN-β (interferon-β) promoter activation and cleaving the MAVS (mitochondrial antiviral signaling) protein; and secondly, we evaluated their abilities to disrupt the IFN-α-induced signaling by means of ISRE (interferon stimulated response element) activity and the virus trans-rescue assay. For all the analyses, we found that there’s no significant differences between NS3/4A from genotypes 1b and 2a, suggesting that HCV NS3/4A might not play a critical role in the different clinical outcomes of the patients infected by the two studied HCV genotypes. In the second part of this study, we screened for the possible HCV proteins which could augment the negative regulation of IFN signaling. Our preliminary data showed that expression of HCV core and NS4B in a hepatoma cell line increased the SOCS3 mRNA levels, and the expression of NS3/4A, NS4B and NS5A in human monocyte cell line enhanced the expression of cytokine IL-8 and TNF-α, which are all known able to inhibit cellular antiviral activity. The underlying mechanisms for the augmented negative regulation of IFN induced by HCV proteins remain to be elucidated. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/30089 |
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顯示於系所單位: | 微生物學科所 |
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