臺灣博碩士論文加值系統

口蹄疫病毒(Foot-and-mouth disease virus；FMDV)歸類為小核醣核酸病毒科 (Picornaviridae)中的鵝口瘡病毒屬(Aphthovirus)，主要可分為七種血清型以及超過六十七種亞型。其疾病在偶蹄類動物間具有高度的傳染性，可感染種類極為廣泛，包括：牛、豬、羊以及超過七十種野生動物。病毒顆粒內為一單股RNA基因組，其蛋白衣由VP1-VP4四種結構蛋白組成，其中又以VP1 C端G-H loop之高度保留序列(RGD)為誘發免疫之重要位置。
台灣地區曾在1997以及1999年爆發嚴重口蹄疫疫情，並從1997年開始全面施打口蹄疫疫苗。目前所使用之死毒疫苗多經過純化步驟，不含或含有極少量病毒非結構蛋白，主要誘導免疫反應產生抗結構蛋白之抗體。本實驗針對口蹄疫病毒O/Taiwan/97病毒株之VP1、VP2結構蛋白進行基因選殖，利用大腸桿菌系統表現重組蛋白，藉由西方轉漬法(Western blot)確認所誘導之蛋白和施打疫苗之豬隻血清有反應。隨後更進一步構築VP1、VP2結構蛋白N端，C端以及中間區域刪除之載體，同樣利用大腸桿菌表現各蛋白並經鎳離子親和性管柱純化。將全長結構蛋白和各端缺損蛋白作為抗原，利用酵素結合免疫分析法(ELISA)以及西方轉漬法(Western blotting)和施打疫苗以及屠宰場之豬隻血清進行反應，企圖找出結構蛋白上與血清反應之最佳區間。結果顯示，各實驗方法皆發現VP1之C端缺損最顯著降低了和血清的反應，顯示VP1的C端具有重要的反應區間。利用酵素結合免疫分析法(ELISA)偵測則以VP1全長或VP1 N端缺損蛋白反應最佳，而利用西方轉漬法(Western blotting)則以VP2各蛋白質反應較佳，顯示VP1蛋白在具構形的狀態下和抗體反應之效果較佳，而變性之VP2蛋白能暴露出更多反應區間和抗體作用。

Foot-and-mouth disease virus (FMDV), the only member of the genus Aphthovirus in the family Picornaviridae, composed of seven serotypes and more than 67 subtypes. The disease affects domestic cloven-hoofed animals, including cattle, swine, sheep, and goats, as well as more than 70 species of wild animals. The virus particle consists of a single-stranded RNA genome, and its capsid is made up by four different proteins, VP1 to VP4. The major immunodominant site on the virion surface resides on the G-H loop of C-terminal of VP1 which includes a highly conserved Arg-Gly-Asp (RGD) sequence. In Taiwan, a national vaccination program was carried out in 1997, and the FMD antigens used to formulate vaccines usually purified to reduce the non-structural proteins content. In order to demonstrate the optimal regions on structural proteins reacting with antibodies, we cloned the genes encoding structural proteins of VP1 and VP2 of O/Taiwan/97 full length, N-terminal deletion, internal deletion, and C-terminal deletion respectively. Proteins are expressed in E. coli system with subsequent purification using Ni2+ affinity column, and then analyses by ELISA and western blotting. Our results reveal that the reaction with serum is significantly reduced in that with C-terminal deletion, suggesting the existence of epitope within the C-terminal of VP1. In ELISA analysis, VP1 protein is more sensitive to antibodies than that of VP2 protein. In western blot analysis, VP2 protein is more sensitive to antibodies than that of VP1 protein, suggesting that native VP1 full-length and N-terminal deletion proteins are considered to be more responsive to antibodies, and the denatured VP2 protein is more sensitive to antibodies than the denatured VP1 protein.

中文摘要 ..................................................................................................i
英文摘要 ..................................................................................................ii
目次 .........................................................................................................iii
圖次 .........................................................................................................vi
第一章 序言 .............................................................................................1
第二章 文獻探討 ......................................................................................3
第一節 口蹄疫之歷史背景 ........................................................................3
第二節 傳染途徑以及臨床症狀 .................................................................4
第三節 口蹄疫病毒結構與分類 .................................................................6
第四節 口蹄疫病毒基因組成 .....................................................................6
第五節 口蹄疫病毒之結構蛋白 .................................................................9
第六節 口蹄疫病毒之非結構蛋白 .............................................................10
第七節 宿主免疫反應 ...............................................................................12
第八節 疾病控制 ......................................................................................14
圖表 ...................................................................................16
第三章 材料與方法 ..................................................................................17
第一節 VP1 VP2基因原核表現載體之構築 ....................17
一 口蹄疫病毒VP1 VP2結構蛋白基因的選殖 ........................................17
1. 聚合酵素連鎖反應 ( polymerase chain reaction, PCR) ..................... 17
2. 瓊脂凝膠的製作 ..................................................................................18
3. DNA 瓊脂電泳分析 (Agarose gel electrophoresis of nucleic acid) .........18
4. DNA片段純化 ......................................................................................19
二 原核表現載體之構築 ...........................................................................19
1. 限制酵素切割 .......................................................................................19
2. 酒精沉澱 ..............................................................................................20
3. 接合反應 (Ligation) ..............................................................................20
4. 勝任細胞製備 (Competent cell) ............................................................20
5. 轉型作用 (Transformation) ....................................................................21
6. 菌株之挑選與質體抽取 ..........................................................................21
7. 限制酵素切割確認與定序 ......................................................................22
第二節 口蹄疫病毒VP1基因各端缺損片段質體之構築 .............................22
一 pET21d-FMDV-VP1△C 質體之構築 ....................................................22
二 pET21d-FMDV-VP1△N 質體之構築 ....................................................23
三 pET21d-FMDV-VP1△I 質體之構築 ......................................................24
四 各質體的確認及定序 ...........................................................................25
第三節 口蹄疫病毒VP2基因各端缺損片段質體之構築 ..............................26
一 pET21d-FMDV-VP2△C質體之構築 ......................................................26
二 pET21d-FMDV-VP2△N質體之構築 .......................................................27
三 pET21d-FMDV VP2△I 質體之構築 .......................................................28
四 各質體的確認 ........................................................................29
第四節 口蹄疫病毒重組結構蛋白的表現 ......................................................29
一 轉型作用 (Transformation) ......................................................................29
二 Isopropyl-β-D-thiogalactopyranoside (IPTG) 誘導蛋白表現 ...................30
三 蛋白質膠體電泳分析 ...................................................................30
第五節 西方轉漬法 (Western blotting) .........................................................32
第六節 蛋白質純化 ...........................................................................33
第七節 蛋白質濃度測定 ................................................................35
第八節 酵素結合免疫分析法 (ELISA) ..........................................................35
第四章 結果 ........................................................................37
第一節 口蹄疫病毒VP1、VP2結構蛋白原核表現質體之構築......................37
一、聚合酶連鎖反應 ( polymerase chain reaction, PCR) .............................37
二、口蹄疫病毒VP1、VP2結構蛋白原核表現載體之構築 ..........................37
第二節 口蹄疫病毒VP1、VP2重組結構蛋白的表現 ..................................38
第三節 利用鎳離子親和性管柱進行蛋白質純化 ..........................................39
第四節 利用西方轉漬法以anti His-tag抗體偵測重組蛋白 ..........................39
第五節 酵素結合免疫分析法 (ELISA) .........................................................40
第六節 利用西方轉漬法以豬隻血清偵測重組蛋白 .......................................41
圖表 ........................................................................................................43
第五章 討論 ..............................................................................................71
圖表 ............................................................................................75
附錄 ...........................................................................................76
參考文獻 ..............................................................................86

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