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研究生:高麗玲
研究生(外文):Li-LingKao
論文名稱:A型流感病毒H3N2亞型NS1基因的差異對於第一型干擾素反應的影響
論文名稱(外文):The effect of NS1 genetic variations of H3N2 influenza A virus on type I interferon
指導教授:王貞仁王貞仁引用關係
指導教授(外文):Jen-Ren Wang
學位類別:碩士
校院名稱:國立成功大學
系所名稱:醫學檢驗生物技術學系碩博士班
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:107
中文關鍵詞:流感病毒NS1蛋白第一型干擾素
外文關鍵詞:Influenza virusNS1 proteinType I IFN
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A型流感病毒為主要造成全世界性流感的重要致病因子,在人類主要流行的型別為H3N2以及H1N1亞型。流感病毒含有八段負股RNA片段,根據不同種病毒共可合成11或12種病毒蛋白。其中NS基因可合成非結構蛋白NS1,NS1蛋白主要可以藉由抑制宿主免疫反應與促進病毒蛋白的轉譯增進流感病毒的致病性與毒力因子。NS1蛋白最為大家熟知的是宿主細胞所產生的第一型干擾素的拮抗蛋白。我們分析了從1999到2011年由成大醫院分離出的病毒株的NS序列,在演化樹分析中大部分H3N2都落在一個主要演化群(H3 group),除了2002年的變異株(H3 variant, H3v)其自行分出一個變異群(H3v group),在變異群的病毒株都帶有分別在RNA-binding domain 的E71G與Effector domain的V82A的雙點突變。近一步分析NS1上的兩點突變對於第一型干擾素的影響,發現變異群的病毒株會引起較高的IFN-β蛋白產生及IFN-β啟動子活化,而其對於IFN-α與其他病毒株也都有相當的感受性。為了近一步探討E71G與V82A對第一型干擾素的影響,我們建構了不同序列的NS1重組蛋白,發現E71G與雙點突變的NS1重組蛋白與病毒株結果一致在IFN-β 啟動子顯示較高程度的活化,另外,在ISRE啟動子的試驗反而發現帶有任一突變或雙點突變的NS1抑制ISRE啟動子的能力都比未突變的H3 NS1顯著。我們利用置換NS基因的重組病毒分析其生長曲線,發現這些重組病毒的生長能力與野生型分離株相當。故由本次研究發現NS1基因上面的E71G與V82A的突變可能會影響第一型干擾素的反應與其下游反應,而對病毒的初期感染有不利的影響,也可能因此使得在NS基因演化樹分析上只有在變異群的2002年變異株帶有雙點突變,之後的H3N2病毒株並未保留此突變點。由於此雙點突變可影響第一型干擾素的反應,故也可以將此突變點應用於疫苗的發展,這些結果也讓我們更進一步瞭解NS1基因上的變異對於流感病毒致病性的重要性。
Influenza A virus is an important pathogen with worldwide prevalence. The major circulating subtypes are H3N2 and H1N1. Influenza A virus contains 8 negative stranded RNA segments that encode 11 or 12 viral proteins. Among them, NS (non-structural) gene encodes NS1 protein which can increase viral pathogenicity and virulence by regulating viral translation and antagonizing host defense immune responses, especially type I interferon (IFN-α/β) production and antiviral activities of IFN-induced proteins. Our phylogenetic analysis of NS genes of H3N2 viruses from 1999 to 2011 showed that most NS genes fall into one group, H3 group, except that NS genes of 2002 isolates (H3 variants, H3v) were separated into another group, H3v group. Two amino acid changes, E71G in the RNA binding domain and V82A in the effector domain, were identified in NS1 proteins of these 2002 isolates. To test whether these amino acid mutations contribute to IFN response, we investigated IFN-β protein production, IFN-β promoter activity and IFN-α susceptibility of isolates in H3 group and H3v group. The result showed that the H3 variants induced higher IFN-β protein production and IFN-β promoter activity. In addition, the H3 variants showed comparable reduction to other isolates in virus productions when pretreated A549 cell with IFN-α. The result indicated that the two substitutions V82A and E71G in NS1 protein of H3 variants can affect the IFN-β protein level and promoter activation. We further constructed recombinant NS1 protein to elucidate the effect of E71G and V82A mutations on IFN-β and ISRE promoter activity. Recombinant NS1 proteins with E71G or double mutation of E71G/V82A substitution showed higher induction of IFN-β promoter than NS1 protein from H3 group. Interestingly, recombinant NS1 proteins with either substitution exhibited stronger inhibitory effects on ISRE promoter activity when compared with H3 NS1. We further investigated the effect of recombinant virus with difference in NS gene sequence on replication curve. It showed that the replication ability of recombinant virus with different NS gene were similar. Our results indicated that NS1 with E71G and V82A mutations may affect type I IFN response in the IFN-β protein secretion, promoter activation and the downstream pathway of IFN-β which may be the disadvantage to virus infection and lead to disappearance in the later season. The substitutions in NS1 can be applied to vaccine strain development. Our study will be helpful to understand the contribution of NS1 genetic variation to the pathogenesis of influenza viruses.
中文摘要 I
英文摘要 III
致謝 V
目錄 VI
表目錄 VII
圖目錄 VIII
第一章、序論 1
第一節: 流行性感冒病毒之演化及其流行病學 1
第二節: A型流行性感冒病毒基因片段及其蛋白 5
第三節: NS1於A型流感病毒毒力上之影響 11
第四節: 研究動機及目標 19
第二章、材料和方法 22
第一節 流行性感冒病毒株的培養 22
第二節:病毒核酸萃取及聚合酶連鎖反應放大、純化 24
第三節:核酸定序以及病毒序列處理 25
第四節: 病毒定量系統 27
第五節: IFN-β蛋白表現分析 28
第六節:IFN-α感受性實驗 28
第七節:NS構築及NS1重組質體的製造 29
第八節:西方點墨分析法 32
第九節: IFNβ啟動子試驗 32
第十節:NS構築及重組病毒的製造 33
第十一節:統計分析 36
第三章、結果 37
第一節: A型流感病毒H3N2亞型NS基因片段分析 37
第二節: H3N2病毒株對於IFN-α/β反應與NS1序列的相關性 39
第三節: NS1重組蛋白對於IFN-α/β反應與NS1序列的相關性 43
第四節: 不同NS基因的重組病毒對於IFN-α/β反應 45
第四章、討論 48
參考文獻: 56

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