系統識別號 U0026-1608201314225500
論文名稱(中文) 探討新流感之神經胺酸酶酵素特性
論文名稱(英文) Analysis of the neuraminidase of the H1N1/09 pandemic influenza viruses
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 101
學期 2
出版年 102
研究生(中文) 張玉婷
研究生(英文) Yu-Ting Chang
學號 T36004021
學位類別 碩士
語文別 中文
論文頁數 106頁
口試委員 指導教授-王貞仁
中文關鍵字 流感病毒  神經胺酸酶  NA酵素活性 
英文關鍵字 Influenza virus  Neuraminidase  NA activity 
中文摘要 每年流感造成了全球數百萬的人受到嚴重的影響,而A型流感病毒為主要造成全世界性流感的重要致病原因。在A型流感病毒表面具有神經胺酸酶蛋白 (Neuraminidase, NA),其功能主要是切除細胞受體上的唾液酸和流感病毒血球凝集素 (Hemagglutinin, HA) 之間的鍵結,以促進流感病毒的釋放及擴散。本研究中,我們分析了1999到2012年由成大醫院分離出的H1N1病毒株的NA序列,在演化樹當中大部分的2009新型流感H1N1都落於同一的演化群 (clade 1),但是在2010年末至2012年有一新的演化群的出現 (clade 2)。而在clade 1中,2011年的病毒株又自成一群 (clade 1.1)。我們發現所有的2009新型流感H1N1的臨床病毒之NA蛋白和疫苗株 (A/California/07/09) 比較皆具有V106I及N248D的突變,而在clade 2和clade 1.1的病毒株分別帶兩組不同的胺基酸突變: N44S、V241I、N369K及S299A 、I374V。接著,我們進一步分析在NA這幾位點的突變對於NA酵素活性上是否會造成影響,因為臨床病毒株可能會受到流感病毒的其他七段基因影響較不易觀察到這些NA蛋白突變對其酵素活性之影響,所以,我們利用了重組NA蛋白及重組病毒 (reverse genetics viruses) 來分析NA突變對其酵素活性的影響,結果發現NA蛋白或重組病毒同時具有V106I 和N248D的突變時,NA活性會上升;在同時有N44S、V241I和N369K則會造成NA活性下降;而在同時有S299A、I374V則會造成NA活性的上升。另外,由重組病毒的生長曲線顯示,這些NA位點的改變不影響重組病毒的複製。但是,由分析病毒初期的感染性得知,NA同時有V106I 及N248D的突變下,初期感染力會上升,顯示這兩點位點可能對流感病毒進入細胞有幫助。總結,本研究有助於了解NA蛋白位點的改變對於流感病毒進入細胞及釋放的影響。
英文摘要 Influenza is a disease that deeply affects millions of people every year. Influenza A virus is an important pathogen with worldwide prevalence. It encodes the membrane neuraminidase (NA) protein that cleaves sialic acids from cellular receptors to facilitate progeny virus release and to promote the spread of the infection. Our phylogenetic analysis of NA genes of 2009 pandemic and old seasonal H1N1 viruses in Taiwan from 1999 to 2012 revealed that 2009 pandemic H1N1 isolates from 2009 to 2011 fell into one major clade (clade 1), but there were two separate clades in 2011 (clade 1.1 & clade 2). Five amino acids changes, S299A and I374V in clade1.1 and N44S, V241I and N369K in clade 2, were identified in NA proteins of these 2011 isolates. To investigate whether these amino acid mutations influenced their NA activity, selected isolates were tested for NA activity. However, the results showed that the NA activities of the selected isolates were similar which may due to the influence of various genetic backgrounds. To investigate NA activity under same genetic background, reverse genetics 2009 pandemic H1N1viruses in the background of A/PR/8/34 (PR8) (H1N1) with different NA genes were generated. To explore whether these amino acid mutations influenced on the viral fitness, we compared the viral replication of reverse genetics viruses. These reverse genetics viruses showed similar growth kinetics in MDCK cells. When their NA activity was examined, the results showed that the NA double mutants (V106I, N248D) enhanced NA activity, and the NA double mutants (S299A , I374V) also showed enhanced NA activity. In contrast, other NA triple mutants (N44S, V241I, and N369K) showed reduced NA activity. The same results were obtained when examined the cell surface NA activities of eight different NA recombinant proteins. Because the NA protein also facilitates viral entry, we further investigated whether these mutations on NA proteins could influence the viral entry. Faster infection process of the reverse genetics viruses that contained NA double mutants (V106I, N248D) were observed when compared with wild type (A/California/07/09). This study will be helpful to understand contributions of NA genetic variations to influenza virus release and entry.
論文目次 中文摘要 I
英文摘要 III
誌謝 V
目錄 VI
表目錄 VIII
圖目錄 IX
第一章、序論 1
第一節 : 流行性感冒病毒簡介 1
第二節 : A 型流感病毒流行病學及其演化 9
第三節 : NA 蛋白對於病毒複製及傳播的重要性 11
第四節: 研究動機及目標 16
第二章 、材料與方法 19
第一節 細胞與流行性感冒病毒株的培養 19
第二節:流感病毒基因萃取及聚合酶連鎖反應放大、純化 22
第三節:病毒核酸定序以及序列處理分析 25
第四節: 流感病毒NA蛋白之結構預測 26
第五節: NA酵素活性測試 27
第六節: NA重組質體的製造和細胞表面NA活性分析 30
第七節: NA質體構築及重組病毒的製造 36
第八節: 重組病毒特性分析 41
第九節: 統計分析 44
第三章、結果 45
第一節: A型流感病毒H1N1亞型NA基因片段分析 45
第二節: pH1N1/09臨床病毒株之NA 胺基酸突變和其酵素活性的相關性 47
第三節: NA 重組蛋白胺基酸取代和其酵素活性相關性 48
第四節: 不同NA基因的重組病毒之胺基酸取代對於病毒的影響 50
第四章、討論 54
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