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研究生:林永政
研究生(外文):Lin, Yung-Cheng
論文名稱:台灣地區腺病毒之分子流行病學與演化動態分析
論文名稱(外文):Molecular Epidemiology and Phylodynamics of Human Adenovirus in Taiwan
指導教授:劉信孚
指導教授(外文):Liu, Hsin-Fu
口試委員:李君男鄭如茜陳建先許濤
口試委員(外文):Lee, Chun-NanCheng, Ju-ChienChen, Chien-HsienHsu, Todd
口試日期:2016-01-14
學位類別:博士
校院名稱:國立臺灣海洋大學
系所名稱:生命科學暨生物科技學系
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:107
中文關鍵詞:人類腺病毒親源演化演化動態選擇壓力
外文關鍵詞:Human AdenovirusesAcute respiratory tract infectionPhylogeneticPhylodynamicSelection pressure
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病毒不斷的演化中,一旦基因變異或重組出現具有生物意義的變化時,常伴隨著大流行的發生,這樣的流行爆發除了造成對人類生命的威脅外,對於經濟活動也會有相當的影響。因此對病毒演化與變化走向的研究是一個不能被忽視的重點。
病毒性呼吸道感染症對嬰幼兒、老年或免疫缺陷等族群造成嚴重的症狀,甚至病患因此而死亡。人類腺病毒是一個台灣地區急性呼吸道感染最重要的病原之一,根據文獻與實驗數據的回顧,腺病毒的結構(Hexon與Fiber)與非結構蛋白質(E3)正持續的進行演化,也在國際上導致流行的爆發,在我國亦有疑似的重組腺病毒出現。根據我們的監測資料台灣地區分別在1999、2001、2003與2011年分別爆發了腺病毒的流行。
為了對台灣腺病毒的演化與流行病學有進一步的解析,這個論文分為兩部分進行:
(1) 台灣地區腺病毒主要血清型在1983~2005與2011年流行期之基因型的變化與臨床症狀的關聯性。
(2) 以外殼結構性蛋白質hexon與fiber的完整基因序列進行演化分析。執行這個研究我們將以Bayesian法為基礎,配合使用各式新穎的演化分析軟體,對腺病毒進行包括:親緣演化,演化動態(Phylodynamics)及選擇壓力(selection pressure)等的一系列演化遺傳分析,以瞭解腺病毒在我國的演化走向與病毒基因變異的時間點。
研究期間共有四個HAdV-3基因型循環於台灣,分別是3a, 3a2, 3a1與3-7,依時間來看HAdV-3a是1983~1999的主要基因型,而HAdV-3a2則是2001~2005的優勢株,而2000年是優勢株的轉換點。HAdV-3的hexon基因親緣演化分析的結果可以看到1983~2005年間的HAdV-3分離株可以分成兩個群,大部分的HAdV-3a2與HAdV-3-7被歸屬於cluster 2,HAdV-3a則屬於cluster 1。HAdV-3感染的病例年紀大多在七歲以下(78%),主要臨床症狀包括發燒、呼吸道症狀、急性腸胃炎及咽結膜熱等。呼吸道症狀的患者更有半數是肺炎或急性支氣管炎等下呼吸道感染症,而急性腸胃炎只出現在HAdV-3a感染的病例。
2011年爆發流行時,HAdV-3(71.85%)與HAdV-7(15.05%)是兩個主要的血清型,hexon基因的親緣演化分析可以看到不論是HAdV-3與HAdV-7都是表現出高度保留性,但是在HAdV-7的fiber基因則是看到了基因型的改變,我們進而證實了優勢株已經由原先的HAdV-7b轉變成HAdV-7d。這波流行中,主要的臨床診斷為急性扁桃腺炎(54.85%)與支氣管炎(48.06%)。
演化動態分面,以hexon基因估算HAdV-3與HAdV-7的核酸取代速率分別是0.234×10-3 substitutions/site/year (95% HPD: 0.387~0.095×10-3)與1.107×10-3 (95% HPD: 0. 541~1.604); 以fiber基因估算則分別是1.085×10-3 (95% HPD: 1.767~0.486) 與0.132×10-3 (95% HPD: 0.283~0.014)。不論是HAdV-3或HAdV-7,主要的選擇壓力位點都是在hexon基因上,而Bayesian skyline plot (BSP)的結果則是暗示著使用單一基因去評估有效族群數量可能會數量可能會造成估算上的失誤。
本研究是台灣地區第一個對於呼吸道腺病毒之演化過程及演化相關數據的完整報導,我們指出了HAdV-7與HAdV-3 的基因型優勢株在台灣的流行狀況及外殼結構蛋白質的演化動態情況。由我們的研究資料可以知道腺病毒正在持續的演化中,持續的監控腺病毒的演化過程將是有利於疫情的控制。

Acute respiratory tract infection (ARTI) caused by virus is a leading cause for hospitalization of infants, young children, the elderly and immune deficiency individuals. Human Adenoviruses (HAdV) are one of the major pathogens of the ARTI in Taiwan. Reviewing of the previous literature and our preliminary data can clearly indicate that the structure protein (Hexon and Fiber) and non-structural protein (E3 region) of adenovirus are constantly evolving and lead to outbreaks in several countries. A few outbreaks of adenovirus have been surveyed in Taiwan in 1999, 2001, 2003 and 2011.
To better understand the evolution and epidemiology of adenovirus in Taiwan, this study is divided into two parts:
(1) To elucidate the HAdV-3 and HAdV-7 genome type change and its association with clinical features in Taiwan.
(2) Full-length sequence of hexon and fiber coapsid protein was analyzed using series of phylogenetic and dynamic evolution tools.
Results of this study shown there were 4 genome types (Ad3a, Ad3a2, Ad3a1, Ad3-7) found in Taiwan during 1983 - 2005. Chronologically, Ad3a was the major genome type found during the period of 1983 - 1999, while Ad3a2 was the predominant genome type obtained from 2001 to 2005. Both Ad3a and Ad3a2 were of similar proportion in 2000. Phylogenetic analysis of the hexon gene of 23 isolates separated these Ad3 into two clusters. Each cluster had unique nucleotide and amino acid patterns. Most Ad3a2 and Ad3-7 isolates were in cluster 2 and most Ad3a isolates belonged to cluster 1. The clinical features of 65 Ad3 infected patients with assayable medical records were analyzed. Seventy-eight percent cases were less than 7 years old. The clinical manifestations included respiratory tract infections, acute gastroenteritis, hand, foot and mouth disease, febrile convulsion and pharyngoconjunctival fever. Respiratory infections, such as pneumonia and acute bronchitis, accounted for 50.8% (33/65). No Ad3a2 infected cases had acute gastroenteritis while 13% Ad3a infected had acute gastroenteritis (P=0.025).
Six different serotypes were identified in outbreak in 2011 and the species B was predominant (HAdV-3, 71.85%; HAdV-7, 15.05%). The most frequent diagnosis was acute tonsillitis (54.85%) and bronchitis (48.06%). Phylogenetic analysis revealed that hexon protein gene sequences were highly conserved for HAdV-3 and HAdV-7 circulation in Taiwan. However, comparison of restriction fragment length polymorphism (RFLP) analysis and phylogenetic trees of fiber gene in HAdV-7 clearly indicated that the predominant genotype in Taiwan has shifted from 7b to 7d.
Several positive selection sites were observed in hexon protein. The estimated nucleotide substitution rates of hexon protein of HAdV-3 and HAdV-7 were 0.234×10-3 substitutions/site/year (95% HPD: 0.387~0.095×10-3) and 1.107×10-3 (95% HPD: 0. 541~1.604) respectively; those of the fiber protein of HAdV-3 and HAdV-7 were 1.085×10-3 (95% HPD: 1.767~0.486) and 0.132×10-3 (95% HPD: 0.283~0.014) respectively. Phylodynamic analysis by Bayesian skyline plot (BSP) suggested that using individual gene to evaluate the effective population size might possibly cause miscalculation.
In summary, this is the first report of dynamic evolution and selection pressure for Adenovirus in Taiwan. We are clarifying the predominant genotype of HAdV-7 and HAdV-3 in Taiwan. The virus evolution is ongoing, and continuous surveillance of this virus evolution will contribute to the control of the epidemic.

目次

中文摘要 I
ABSTRACT III
目次 V
前言 1
一、 人類腺病毒簡介 1
二、 腺病毒的流行病學概況 3
三、 臨床腺病毒檢驗 5
四、 親緣演化與演化動態分析在病毒研究的應用 5
(1) 距離矩陣法: 7
(2) 特徵法: 7
五、 腺病毒新興與再浮現感染 8
六、 研究目的 9
研究方法 11
檢體收集 11
病毒培養 11
病毒鑑定 12
病毒的純化與核酸萃取 12
(1) 以商業試劑萃取 13
(2) 傳統Phenol/ chloroform/ isoamylalcohol (P/C/I;25:24:1)核酸萃取 13
血清型與基因型分析: 14
PCR 產物純化 15
Hexon與fiber基因核酸定序 15
親緣演化 16
演化壓力分析 18
演化動態與親緣地理分析 19
統計檢定分析 20
結果 22
Part I:1983–2005年腺病毒第三型之分子流行病學分析 22
Part II:2011年腺病毒流行期之分子流行病學分析 23
Part III:腺病毒結構蛋白質(Hexon 與 Fiber)基因演化動態分析 25
(1) 演化速率與共同原始祖先 25
(2) HAdV- 3 and 7 表面結構蛋白質的選擇壓力分析 26
(3) 腺病毒演化動態與親緣地理分析 27
討論 29
結論 36
參考文獻 37
附錄 1:本研究之人體試驗同意書 87
附錄 2:已完發表之期刊全文 88
i. Secular trend of genome types of respiratory adenovirus type 3 during 1983–2005: a study from Taiwan. Arch Virol (2010) 155:287–292 88
ii. Molecular Epidemiology and Phylogenetic Analysis of Human Adenovirus Caused an Outbreak in Taiwan during 2011. PLoS One. 2015 May 18;10(5) 88

圖次
圖 1:疾病管制署2005~2015年台灣地區腺病毒監測資料。 70
圖 2:以RFLP分析 1983~2006年之HAdV-3 基因型。 71
圖 3: HAdV-3 之hexon 區域全長序列之親源演化分析。 72
圖 4:2011年呼吸道腺病毒分離個案數與月份趨勢圖 73
圖 5:以HAdV-7的hexon基因建構親緣演化樹。 74
圖 6:以HAdV-7的fiber基因建構親緣演化樹。 75
圖 7:以HAdV-3的hexon基因建構親緣演化樹。 76
圖 8:以HAdV-3的fiber基因建構親緣演化樹。 77
圖 9:以RFLP分析HAdV-7 基因型。 78
圖 10:以HAdV-7的hexon基因建構親MCC 樹。 79
圖 11:以HAdV-7的fiber基因建構親MCC 樹。 80
圖 12:以HAdV-3的hexon基因建構親MCC 樹。 81
圖 13:以HAdV-3的fiber基因建構親MCC 樹。 82
圖 14:以hexon 基因建構的HAdV-3的族群演化動態。 83
圖 15:以fiber基因建構的HAdV-3的族群演化動態。 84
圖 16:以hexon基因建構的HAdV-7的族群演化動態。 85
圖 17:以fiber基因建構的HAdV-7的族群演化動態。 86

表次
表 一:設計專一性引子對用以放大與定序Hexon與Fiber基因。 50
表 二:1983~2005年間呼吸道腺病毒分離概況 51
表 三:以RFLP進行1983-2005年間HAdV-3分離株之基因型分析 52
表 四:1983~2005年間HAdV-3分離株於親緣演化樹之分群 53
表 五:比較HAdV-3的兩個cluster間,胺基酸與核苷酸之差異 55
表 六:論文中用來建構親緣演化樹與演化動態分析的參考序列表。 56
表 七:1992~ 2005年間 HAdV-3感染病患之臨床資料統計表 63
表 八:2011年呼吸道腺病毒陽性個案的人口學與臨床統計資料 64
表 九:HAdV- 3與HAdV- 7結構性蛋白質的演化速率與共同原始祖先時間 67
表 十:HAdV- 3 與HAdV- 7的結構性蛋白質的選擇位置偵測。 69



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