臺灣博碩士論文加值系統

摘 要
在臺灣，正番鴨、鵝小病毒感染症常造成鴨與鵝幼禽嚴重死亡，成禽甚至有生長遲緩、增重率差之情形，因而導致家禽業重大的經濟損失。目前尚未有疫苗可供使用，致使此疾病成為本省水禽之一大危害。根據文獻報導鴨、鵝小病毒之結構蛋白VP2可於昆蟲細胞中自行組裝(self-assemble)成類病毒顆粒(virus-like particles, VLPs)，因此，本實驗之目的即是利用昆蟲細胞培養/桿狀病毒表現系統(Insect cell culture / baculovirus expression system )表現此病毒之結構蛋白作疫苗使用。為了評估VLPs之免疫效力，分別於一週和三週齡時，對鴨、鵝進行免疫試驗，實驗分成二組即免疫組與對照組，免疫兩次之後於六週齡進行攻毒試驗。另外，由於傳統之病毒定量方法，較難應用在此兩病毒上，故利用定量PCR (quantitative polymerase chain reaction)技術來分析尿囊液中所含小病毒之核酸量。分析之後，取0.2 ml劑量（約含2.64 ×10 6個病毒）以點眼點鼻方式，對鴨隻進行攻毒試驗。為了能有效評估試驗結果，於攻毒後二天分別以multi-screen channel西方轉漬法、鴨隻體重之增加量，以及PCR偵測糞材中鴨隻之排毒等方式作分析，結果發現，免疫組於第二次免疫後一週即開始有抗VP2之抗體產生，至攻毒後十天抗體達最高峰；而對照組只有在攻毒後一週可看見訊號產生，且訊號明顯較為微弱。另外免疫組在攻毒後3~ 6日內之體重增加顯著高於對照( p > 0.05)。但是利用PCR所偵測到之排毒鴨隻數目，在免疫組與對照組並無顯著差異。由以上結果得知，以重組VP2蛋白所製成之疫苗，對於鴨隻僅具有部分保護效果，即免疫組比對照組有較佳之增重率，但卻無法減少鴨隻糞便中之排毒情形。

Abstract
In Taiwan, the infection of Muscovy duck and goose parvovirus not only lead to a high mortality of ducklings and goslings, but also affect the growing and weight gaining rate of the adult birds. These diseases could cause severe financial losses in the poultry industry. However, there is no effective vaccine available for the control of these diseases, and thus these diseases have been a major threat to waterfowls in Taiwan. According recent reports, recombinant VP2 capsid protein of MDPV expressed by baculovirus expression system could self-assemble and form virus-like particles ( VPLs) in insect cells. Thus, the goal of this study is to use the insect cell culture/ baculovirus expression system to express the VP2 capsid protein of MDPV and GPV for the preparation of vaccine. In order to evaluate the immunity induced by the VLPs, vaccination experiment were performed on ducks and geese. Birds were divided into two groups, vaccinated group and control group. Vaccinations were conducted when birds were one and three weeks old, and challenge was conducted when birds were six weeks old. Because of the difficulty in the determination of the virus titers of GPV and MDPV, we used quantitative PCR technique to determine the copy number of genome of GPV and MDPV, and challenged the ducks by intranasal inoculation of 0.2 ml allantonic fluids containing 2.64 x 106 genome equivalent MDPV. The efficacy of vaccine was evaluated by multi-screen channel Western blot, body weight gaining of ducks, and PCR detection for the presence of virus in the feces. We found that, in the vaccinated group, the antibody against VP2 was produced in one week after the second vaccination, and the titer reached the plateau on the 10th day after challenge. In contrast, in the control group, the antibody against VP2 was detected only after the challenge, and the signal was weaker than that of the vaccinated group. In addition to the difference in the antibody response, the amount of body weight gained in the vaccinated group was significantly higher than that of the control groups in 3-6 days after challenge ( p < 0.05). However, no difference was observed between the vaccinated and control groups regarding the number of ducks that shed viruses in feces. These results indicate that the recombinant VP2 protein could provide only a partial protection against challenge of virus. In other words, the recombinant VP2 protein could provide a better body weight gaining but could not prevent ducks from shedding virus in feces.

目 次
中文摘要 ……………………………………………………… Ⅰ
Abstract ……………………………………………………… Ⅱ
目次 ……………………………………………………… Ⅲ
表次 ……………………………………………………… Ⅵ
圖次 ……………………………………………………… Ⅵ
第一章 緒言………………………………………………… 1
第二章 文獻探討…………………………………………… 3
第一節 鴨、鵝小病毒之歷史背景………………………… 3
第二節 鴨、鵝鵝小病毒之特徵…………………………… 4
2-1 分類………………………………………………… 4
2-2 型態與結構………………………………………… 5
2-3 物理與化學性質…………………………………… 5
2-4 宿主範圍、臨床症狀與病理變化………………… 5
第三節 小病毒之基因體與複製…………………………… 6
3-1 小病毒之基因體…………………………………… 6
3-2 小病毒之感染與複製過程………………………… 7
第四節 小病毒之非結構蛋白與結構蛋白………………… 8
4-1 小病毒非結構蛋白質之功能……………………… 8
4-2 小病毒之結構蛋白( VP1、VP2、和VP3)性狀分析 9
4-3 台灣地區小病毒核酸之序列比對………………… 12
第五節 鴨和鵝小病毒感染症之預防與診斷……………… 12
5-1 鴨、鵝小病毒感染症之預防方法………………… 12
5-2 小病毒疫苗研發之現況…………………………… 13
5-3 鴨和鵝小病毒感染症之診斷方法………………… 15
第六節 桿狀病毒之特徵…………………………………… 16
6-1.1 分類………………………………………………… 16
6-1.2 桿狀病毒之型態與基因體………………………… 17
6-1.3 生活史……………………………………………… 18
6-1.4 桿狀病毒之基因調控……………………………… 19
6-1.5 桿狀病毒表現載體系統之介紹…………………… 20
6-2 桿狀病毒之繼代效應……………………………… 22
第七節 定量PCR之應用原理…………………………….. 23
7-1 定量PCR之基本介紹…………………………….. 23
7-2 定量PCR與螢光染劑系統………………………... 23
7-3 TaqMan探針系統之設計與功能………………….. 23
7-3.1 探針之設計………………………………………… 24
7-3.2 TaqMan探針於PCR反應中之作用……………… 24
第三章 材料與方法………………………………………… 25
第一節 MDPV與GPV去氧核醣核酸萃取………………. 25
第二節 重組表現載體之構築……………………………… 25
2-1.1 引子( primer)之設計……………………………….. 25
2-1.2 聚合酶連鎖反應( PCR)增幅基因之條件…………. 26
2-1.3 PCR產物之電泳分析……………………………… 27
2-2 重組基因之選殖……………………………………. 27
2-2.1 接合反應( ligation)………………………………….. 27
2-2.2 重組質體之轉型作用( transformation)…………….. 28
2-2.3 質體之抽取與確認……………………………….. 28
2-3 第二次重組基因之選殖…………………………… 29
2-3.1 載體的製備……………………………………….. 29
2-3.2 接合作用( ligation)…………………………………. 29
2-3.3 勝任細胞( competent cells)之製備…………………. 29
2-3.4 重組置換載體之轉型作用…………………………. 30
第三節 重組桿狀病毒病毒之挑選與確認………………….. 30
3-1 線性化桿狀病毒與重組置換載體之共同轉染作用.. 30
3-2 純化重組桿狀病毒之病毒溶斑試驗( plaque assay).. 31
3-3 以PCR檢測純化後之重組桿狀病毒……………… 31
3-3.1 重組桿狀病毒核酸之萃取…………………………. 31
3-3.2 以PCR檢測純化後之重組桿狀病毒……………… 31
3-3.3 聚合酶連鎖反應(PCR)增幅基因之條件…………… 32
3-3.4 PCR產物之電泳分析與定序確認…………………. 33
第四節 病毒蛋白之表現與確認……………………………. 33
4-1 昆蟲細胞株之來源與培養方式………………… 33
4-2 高力價重組桿狀病毒之培養與病毒力價之評估….. 33
4-2.1 重組桿狀病毒之增幅………………………………. 33
4-2.2 病毒力價之評估……………………………………. 34
4-3 重組蛋白表現時間最佳化之評估與確立………….. 34
4-3.1
4-3.2 重組蛋白表現時間最佳化之分析………………….
重組蛋白之電泳分析與確認………………………. 34
34
4-4 以間接螢光抗體偵測重組蛋白於細胞內之分佈…. 35
第五節 免疫試驗製劑之製作與攻毒試驗劑量之評估…… 36
5-1 油質乳劑疫苗之製備……………………………… 36
5-1.1 抗原之置備………………………………………… 36
5-1.2 疫苗之製作……………………………………….. 36
5-1.3 疫苗接種…………………………………………… 36
5-2 攻毒方式與實驗步驟……………………………… 37
5-3 以定量PCR估計攻毒劑量中小病毒之含量….…. 37
5-3.1 定量PCR標準曲線之建立……………………….. 37
5-3.2 定量PCR產物之分離曲線分析………………….. 38
第六節 免疫及攻毒試驗結果之評估……………………… 40
6-1 以西方轉漬法分析血清中之抗體力價…………… 40
6-2 測量免疫及攻毒試驗期間個體之重量變化…….. 41
6-3 以PCR偵測糞材中小病毒排毒之情形…………... 41
6-3.1 糞材中病毒DNA之萃取………………………… 41
6-3.2 聚合酶連鎖反應( PCR)增幅基因之條件………….. 42
6-3.3 PCR產物之電泳分析…………………………….… 43
第四章 實驗結果……………………………………………. 44
第一節 重組質體構築之確認………………………………. 44
第二節 重組桿狀病毒之挑選與確認………………………. 44
2-1 純化重組桿狀病毒之病毒溶斑試驗……………….. 44
2-2 以PCR檢測純化後之重組桿狀病毒………………. 45
第三節 重組蛋白之電泳分析與確認……………………….. 45
第四節 攻毒劑量之評估…………………………………….. 46
4-1 定量PCR標準曲線之建立…………………………. 46
4-2 攻毒劑量之確立…………………………………….. 46
第五節 免疫及攻毒試驗結果之評估……………………….. 47
5-1 以西方轉漬法偵測血清中之抗VP2抗體……… 47
5-2 免疫及攻毒試驗期間免疫組與對照組之體重變化. 47
5-3 以PCR偵測糞材中小病毒排毒之情形…………… 48
第五章 討論…………………………………………………. 66
參考文獻 ………………………………………………………. 72
表次
表一 本研究中鴨、鵝小病毒分離株之來源與分離時間… 49
表二 免疫及攻毒試驗免疫組與對照組之平均總體重 SAS分析表…………………………………………...
50
表三 免疫及攻毒試驗免疫組與對照組之平均增重差之 SAS分析表…………………………………………...
50
圖次
圖一 小病毒之序列與其所表現蛋白質之位置示意圖.. 51
圖二 重組置換載體之構築流程圖…………………….. 52
圖三 置換載體pBlueBacHis2A/MDPV/GPV以限制酵素( Bam HI/ Sal I)切割之電泳分析圖…………….
53
圖四 線性化之桿狀病毒與鴨源及鵝源之置換載體，
藉由同源重組原理，將VP2基因整入至桿狀病毒中之示意圖………………………………………..
54
圖五 重組病毒溶斑形成之過程……………………….. 55
圖六 病毒溶斑試驗純化重組桿狀病毒之結果……….. 56
圖七 以PCR技術鑑定重組桿狀 病毒之電泳分析圖.. 57
圖八 重組蛋白之電泳分析與確認……………………. 58
圖九 定量PCR技術偵測嵌有VP2之質體DNA……. 59
圖十 由已知濃度標準含VP2基因之重組質體所建立之標準曲線………………………………………
60
圖十一 定量PCR技術偵測尿囊液中未知之病毒含量…. 61
圖十二 定量PCR產物之分離曲線………………………. 62
圖十三 以 multi-screen channel 西方轉漬法分析免疫及攻毒試驗鴨血清中之抗體………………………..
63
圖十四 免疫及攻毒試驗鴨隻之總重量與增重差比較圖.. 64
圖十五 以 PCR 偵測糞材中小病毒排毒之統計圖……... 65

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