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系統識別號 U0026-1601201218050300
論文名稱(中文) 探討新流感與季節性流感病毒受體結合特性
論文名稱(英文) Analysis of Receptor Binding Property of Pandemic & Seasonal H1N1 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 100
學期 1
出版年 101
研究生(中文) 林政義
研究生(英文) Cheng-Yee Lim
學號 T36985015
學位類別 碩士
語文別 中文
論文頁數 96頁
口試委員 指導教授-王貞仁
口試委員-劉校生
口試委員-林貴香
口試委員-張權發
中文關鍵字 流感病毒  新流感H1N1  季節性流感H1N1  血球凝集素  受體結合  神經胺酸酶活性 
英文關鍵字 influenza virus  pandemic H1N1  seasonal H1N1  Hemagglutinin  receptor binding  NA activity 
學科別分類
中文摘要 每年流感病毒都造成全球數百萬人的感染,在臨床上,流感病毒感染除了可以觀察到一些呼吸道的症狀,嚴重的話會造成肺炎或導致死亡。流感病毒表面具有血球凝集素(Hemagglutinin,HA),在頂端部分具有一個受體結合位置,主要是辨識宿主細胞表面的唾液酸(N-acetyl Neuraminic Acid, Neu5Ac)受體進而感染宿主。在H1病毒中,受體結合位置上的這些氨基酸是具有高度保留性的,有許多文獻指出,這些氨基酸決定了病毒對於α2-3 和 α2-6結構的唾液酸的親和力。在2009年4月,墨西哥爆發新流感H1N1(pandemic influenza H1N1)疫情,而且很快地經由人傳人的方式傳播到全世界。在他人研究中指出,這株病毒是由豬、禽、人流感病毒重組而形成的,其中HA基因是來自豬流感病毒。經由序列分析,我們發現在新流感與季節性流感病毒的受體結合位置有許多氨基酸差異的位點,所以我們想要研究這些差異對於新流感與季節性流感病毒的受體結合能力之影響。我們利用受體結合實驗(receptor binding assay)去觀察新流感與季節性流感病毒對於galactose或lactosamine以α2-3結構連結的唾液酸受體(Neu5Acα2-3Gal or Neu5Acα2-3LacNAc)和galactose或lactosamine以α2-6結構連結的唾液酸受體(Neu5Acα2-6Gal or Neu5Acα2-6LacNAc)的親和力。我們發現新流感病毒對受體結合的能力和季節性流感是相似的,尤其是對於較長的醣類(Neu5Acα2-3LacNAc和Neu5Acα2-6LacNAc)。之後,我們在與細胞結合的平台觀察新流感與季節性流感的結合能力,也發現結果與glycan的結合有相關性。除此之外,我們也去探討它們之間的神經胺酸酶(Neuraminidase,NA)的活性,NA主要在病毒複製完後切除它和細胞表面的連結,我們看到新流感具有高NA活性。因此,我們認為新流感的爆發與它具有和季節性流感相若的受體結合能力再加上高NA活性的平衡有關。這些結果有助於我們更了解流感病毒的感染與傳播。
英文摘要 Influenza virus causes epidemics worldwide that affect millions of people annually. Clinical spectrums of influenza virus infections range from mild respiratory tract infection to severe pneumonia and death. The membrane hemagglutinin (HA) glycoprotein is the receptor-binding protein that targets to cell surface receptors containing sialic acid (N-acetyl Neuraminic Acid, Neu5Ac). Amino acids that comprise this receptor binding site is a pocket located on the distal end of HA molecule and are highly conserved among numerous H1 influenza viruses. Numerous reports have demonstrated that amino acids of receptor-binding domain of HA protein contributes to its relative binding affinities for α2-3 or α2-6 linked receptors. In April 2009, the first outbreak of pandemic influenza H1N1 in Mexico spreaded rapidly across the world via human-to-human transmission. It has been reported that reassorted pandemic H1N1 virus containing HA gene originated from swine and other RNA segments from swine, avian and human. Our sequence analysis revealed a lot of amino acid variations in receptor-binding sites between pandemic and seasonal H1N1 viruses. To investigate whether pandemic H1N1 viruses display differential receptor binding ability, we first determined the binding affinity of seasonal and pandemic H1N1 for N-acetyl neuraminic acid linked to galactose or lactosamine by α2-3 linkage (Neu5Acα2-3Gal or Neu5Acα2-3LacNAc) or by α2-6 linkage (Neu5Acα2-6Gal or Neu5Acα2-6LacNAc) by receptor binding assay. We found that the receptor binding ability of pandemic H1N1 is close to binding ability of seasonal H1N1, especially the longer glycan (Neu5Acα2-3LacNAc & Neu5Acα2-6LacNAc). In addition, we performed the binding assay of pandemic and seasoanal H1N1 to cells (MDCK, A549, DF-1 & TWO1), and found that the binding profiles were similar and correlated with glycan binding result. Furthermore, we examined their NA activity which is related to virus releasing from the cell surface, pandemic H1N1 showed higher NA activity. In conclusions, we demonstrate that pandemic H1N1 with similar binding affinity as seasonal H1N1 and the higher NA activity may be responsible for higher transmission which results in 2009 pandemic and afterward. These findings may help us in understanding the influenza virus infection and transmission.
論文目次 中文摘要 I
英文摘要 III
致謝 V
目錄 VI
第一章、 序論 1
一、 流行性感冒病毒及其特性 1
1) 流行性感病毒之結構特性及分型 1
2) A型流感病毒之基因及其病毒蛋白 2
二、 流感病毒之流行病學與演化 6
1) 流感病毒之流行病學 6
2) 流感病毒之演化與新型流感病毒 7
3) 流行性感冒的預防與治療 10
三、 HA蛋白對病毒感染之重要性 12
1) 病毒HA與受體結合特異性及其宿主範圍 12
2) HA與受體結合特性檢測分析平台 14
四、 研究動機及目標 15
第二章、 材料與方法 17
一、 細胞與流行性感冒病毒株的培養 17
二、 流感病毒HA基因片段之萃取、放大及純化 20
三、 病毒核酸定序及序列之處理分析 22
四、 流感病毒受體結合實驗 (Receptor binding assay) 23
五、 利用流式細胞儀分析細胞表面之唾液酸結構 25
六、 流感病毒與細胞結合實驗(Virus-cell binding assay) 26
七、 流感病毒神經胺酸酶活性試驗(Neuraminidase activity assay) 28
八、 流感病毒表面醣蛋白HA之結構預測 30
九、 統計方法 30
第三章、 實驗結果 31
一、 探討季節性流感seasonal H1N1與新型流感pandemic H1N1病毒對於α2-3 和α2-6鍵結方式唾液酸的結合特性; 31
1) 流感病毒HA & NA基因演化樹分析 31
2) 比較seasonal和pandemic H1N1對於Neu5Acα2-3Gal 和Neu5Acα2-6Gal的親和力 32
3) 比較seasonal和pandemic H1N1對於Neu5Acα2-3LacNAc和Neu5Acα-2-6LacNAc的親和力 33
二、 探究造成seasonal和pandemic H1N1受體結合能力差異的決定位點; 34
三、 比較receptor binding assay和病毒與細胞結合實驗(virus-cell binding assay)的binding結果; 38
1) 各種細胞株α2-3及α2-6受體表現量 38
2) 建立病毒與細胞結合實驗(virus-cell binding assay) 39
3) 比較receptor binding assay 和virus-cell binding assay的結果 40
四、 探討seasonal和pandemic H1N1的NA活性差異。 41
第四章、 討論 45
參考文獻 51
作者簡歷 96


表目錄
表一、H1N1病毒HA在與Neu5Acα2-6Galβ1-4GlcNAc結合有關之氨基酸位點異同處 61
表二、Seasonal與pandemic H1N1在與NA activity有關之氨基酸位點異同處 62

圖目錄
圖一、2000年至2011年seasonal 和pandemic H1N1病毒株之HA基因演化樹分析 63
圖二、2000年至2011年seasonal和pandemic H1N1病毒株之NA基因演化樹分析 64
圖三、Seasonal和pandemic H1N1病毒株與Neu5Acα2-3Gal-PAA (SAα2-3Gal-)的親和力 65
圖四、Seasonal和pandemic H1N1病毒株與Neu5Acα2-6Gal-PAA (SAα2-6Gal-)的親和力 66
圖五、Seasonal和pandemic H1N1 病毒株與Neu5Acα2-3LacNAc-PAA (SAα2-3LacNAc-)的親和力 67
圖六、Seasonal和pandemic H1N1病毒株與Neu5Acα2-6LacNAc-PAA (SAα2-6LacNAc-)的親和力 68
圖七、利用flow cytometry分析α2-3 與α2-6的glycan在各個細胞株表面分佈狀況 69
圖八、利用Virus Quantification-ELISA方法定量庫存病毒量 70
圖九、Seasonal和pandemic H1N1病毒與MDCK細胞株的結合情況 71
圖十、Seasonal和pandemic H1N1病毒與A549細胞株的結合情況 72
圖十一、Seasonal 和pandemic H1N1病毒與DF-1細胞株的結合情況 73
圖十二、Seasonal和pandemic H1N1病毒與TWO1細胞株的結合情況 74
圖十三、Neu5Acα2-6LacNAc和Neu5Acα2-3LacNAc receptor binding assay與Cell binding assay結果之間的關聯性 75
圖十四、Neu5Acα2-6Gal和Neu5Acα2-3Gal receptor binding assay與Cell binding assay結果之間的關聯性 76
圖十五、比較seasonal和pandemic H1N1之間NA的活性 77

附錄
附錄一、流感病毒之(A)結構及(B)其複製週期 78
附錄二、Pandemic H1N1 2009的起源 79
附錄三、世界衛生組織(WHO)建議之流感疫苗病毒株 80
附錄四、Receptor binding assay的流程圖與受體的結構圖 83
附錄五、Virus Quantification – ELISA定量病毒的流程圖 84
附錄六、Virus-cell Binding Assay之流程圖 85
附錄七、NA activity assay流程圖 86
附錄八、國立成功大學附設醫院病毒實驗室A型流感病毒統計圖 87
附錄九、H1N1之臨床病毒株 88
附錄十、國立成功大學附設醫院病毒實驗室(NCKUH)流感病毒分離株HA及NA基因片段定序流程 89
附錄十一、流感病毒HA上的受體結合位置(RBS)之結構圖 90
附錄十二、Glycan與HA結合模擬圖 91
附錄十三、儀器 92
附錄十四、藥品 94

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