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研究生:李光琇
研究生(外文):Kuang-Hsiu Lee
論文名稱:以抗HA單源抗體建立阻斷型ELISA區別抗禽流感病毒H5或H6亞型之抗體
論文名稱(外文):Differentiation of Antibodies Against H5 and H6 Influenza A Viruses by Blocking ELISA Using Anti-HA Monoclonal Antibodies
指導教授:鄭益謙
指導教授(外文):Ivan-Chen Cheng
口試委員:王金和張伯俊鄭明珠趙裕展
口試委員(外文):Ching-Ho WangPoa-Chun ChangMing-Chu ChengYu-Chan Chao
口試日期:2015-07-24
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:獸醫學研究所
學門:獸醫學門
學類:獸醫學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:138
中文關鍵詞:禽流感病毒血球凝集素單源抗體桿狀病毒表現蛋白阻斷型酵素聯結免疫吸附法
外文關鍵詞:avian influenza virus (AIV)hemagglutinin (HA)monoclonal antibody (MAb)baculovirusprotein expressionblocking ELISA (bELISA)
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H6N1及H5N2禽流感病毒 (avian influenza virus, AIV) 分別於1972及2003年出現於台灣並且流行至今,H6N1 AIV的分離株為低病原性,而H5N2 AIV在近幾年已經從感染的雞隻分離到高病原性的病毒,必須要發展出可以區分雞隻血清中帶有抗H5或H6亞型之抗體的檢測工具,以幫助AIV的監測與防疫。本研究以不活化的H5N2或H6N1 AIVs免疫BALB/c小鼠,待小鼠血清力價上升後,以融合瘤技術將脾臟細胞 (splenocytes) 與骨髓瘤細胞 (myelomas) 進行融合,並利用間接螢光抗體染色法 (indirect immunofluorescent assay, IFA)、血球凝集抑制試驗(hemagglutination inhibition test, HI test)、中和試驗 (Neutralization test, NT)、西方墨點法 (Western blot, WB) 及間接型酵素連結免疫吸附法 (indirect ELISA) 篩選出抗血球凝集素 (hemagglutinin, HA) 之單源抗體 (αHA MAbs),同時鑑定αHA MAbs對H5與H6 AIV抗原之間沒有交叉反應;另一方面,我們使用福馬林不活化的A/chicken/Taiwan/1209/2003(H5N2) 全病毒,與桿狀病毒表現系統所表現的A/chicken/Taiwan/2838V/00(H6N1) HA蛋白 (rHAΔTM/H6N1) 作為抗原,搭配經過篩選的αHA MAbs,挑選出最佳的抗體組合,建立以1209/H5N2或rHAΔTM/H6N1為抗原的sandwich blocking ELISA (1209/H5N2 bELISA與rHAΔTM/H6N1 bELISA)。以HI test作為雞血清樣本中H5、H6亞型抗體存在與否的黃金標準 (golden standard),以702個雞血清測試兩種bELISA,1209/H5N2 bELISA的臨界值為27%,敏感性為93.31% (265/284),特異性為90.91% (380/418);rHAΔTM/H6N1 bELISA的臨界值為28%,敏感性為95.11% (214/225),特異性為96.44% (460/477)。此兩種bELISA相對於HI test具有較高的敏感性,可檢測到低HI力價的血清抗體,有助於提升國內禽流感血清檢測與防疫監測之成效。

H6N1 and H5N2 AIV have been circulated in Taiwan since 1972 and 2003 respectively. H6N1 strains are low pathogenic avian influenza viruses (LPAIV). However, some of the H5N2 strains isolated currently become highly pathogenic avian influenza viruses (HPAIV). Developing an effective detection tool to differentiate whether the serum antibodies are against H5 or H6 subtypes is essential for AIV surveillance and management. In this study, BALB/c mice were immunized with inactivated H5N2 or H6N1 AIVs. After evaluated the antibody titer of the mice sera by immunofluorescent assay (IFA), we fused mice splenocytes with myelomas to generate hybridomas. Anti-HA Monoclonal antibodies (αHA MAbs) were screened by IFA, hemagglutination inhibition (HI) assay, western blotting (WB) and indirect ELISA (iELISA) to confirm the specificity to HA and no interaction between H5 and H6 AIVs. On the other hand, we established two sandwich blocking ELISAs (1209/H5N2 bELISA;rHAΔTM/H6N1 bELISA) with αHA MAbs and formalin-inactivated 1209/H5N2 viruses or recombinant HA protein of A/chicken/Taiwan/2838V/00 (H6N1) by baculovirus-insect cell expression system. Hemagglutination inhibition test was taken as the golden standard method of detecting anti-H5 or anti-H6 antibodies in the chicken sera. 702 chicken sera were tested by 1209/H5N2 bELISA and rHAΔTM/H6N1 bELISA. The cut-off value of 1209/H5N2 bELISA was 27%. The sensitivity and specificity were 93.31% (265/284) and 90.91% (380/418). In addition, the cut-off value of rHAΔTM/H6N1 bELISA was 28%. The sensitivity and specificity were 95.11% (214/225) and 96.44% (460/477). Also, both of the two bELISAs can detect the antibodies in chicken sera with low HI titer. The results show that these bELISAs could be used to differentiate H5 and H6 infection in the field.

口試委員會審定書 i
誌謝 ii
摘要 v
Abstract vi
目錄 vii
圖目錄 xiv
表目錄 xvi
第一章 序言 1
第二章 文獻回顧 3
第一節 禽流感之起源 3
第二節 流感病毒之介紹 3
第三節 台灣禽流感疫情 5
第四節 流感病毒之複製 6
第五節 血球凝集素 (HA) 之介紹 7
2-5.1 H亞型之分類 7
2-5.2 HA0之結構與功能 7
2-5.3 HA1之結構與功能 8
2-5.4 HA2之結構與功能 10
2-5.5 HA醣基化之構造與功能 11
第六節 Bromelain cleaved HA (BHA)與recombinant HA (rHA) 12
第七節 AIV之診斷 13
2-7.1 AIV之抗原診斷 13
2-7.2 AIV之抗體診斷 13
第八節 Influenza virus之治療方法 14
第九節 桿狀病毒-昆蟲細胞表現系統 (Baculovirus-insect cell expression system) 14
第三章 材料與方法 16
第一節 細胞培養與繼代 16
3-1.1 MDCK細胞 16
3-1.2 Sf9細胞 16
第二節 病毒培養與力價測定 17
3-2.1 病毒分離株 17
3-2.2 病毒增殖與不活化 17
3-2.3 病毒液濃縮與純化 17
3-2.4 血球凝集試驗 (HA test) 18
3-2.5 病毒力價測試 (Viral titration) 18
第三節 抗H5N2禽流感病毒血球凝集素之融合瘤單源抗體製備 19
第四節 抗H6N1禽流感病毒血球凝集素之融合瘤單源抗體製備 19
3-4.1 免疫計畫 19
3-4.2 骨髓瘤細胞培養 (myeloma cell culture) 20
3-4.3 融合瘤製備 20
3-4.4 親代融合瘤細胞篩選 21
3-4.4.1 免疫螢光染色法 (IFA) 21
3-4.4.2 血球凝集抑制試驗 (HI test) 22
3-4.5 融合瘤細胞單株化及命名 22
第五節 αHA單源抗體之特性鑑定與製備 23
3-5.1 免疫螢光染色法 (IFA) 23
3-5.2 血球凝集抑制試驗 (HI test) 23
3-5.3 中和試驗 (Neutralization test) 24
3-5.4 西方墨點法 (Western blot) 24
3-5.4.1 製備AIV接種之MDCK cell lysate 24
3-5.4.2 還原性與非還原性西方墨點法 (Reducing WB & Non-reducing WB) 25
3-5.5 單源抗體之亞型分析 (Isotyping) 26
3-5.6 腹水製備 26
3-5.7 單源抗體之純化 26
3-5.8 單源抗體之定量 27
3-5.9 單源抗體之酵素標示 (HRP-conjugation) 28
第六節 rHAΔTM/H6N1抗原製備與確認 28
3-6.1 重組rHAΔTM/H6N1基因之選殖 28
3-6.1.1 RNA萃取 28
3-6.1.2 反轉錄作用 (Reverse transcription, RT) 29
3-6.1.3 聚合酶鏈鎖反應 (PCR) 增幅2838/H6N1 full-length HA gene 29
3-6.1.4 Blunt-end cloning 30
3-6.1.5 重組載體pJET1.2-HA之轉型作用 (Transformation) 31
3-6.1.6 Colony PCR 31
3-6.1.7 轉殖菌體之保存 32
3-6.1.8 重組載體pJET1.2-HA之萃取 32
3-6.1.9 聚合酶鏈鎖反應 (PCR) 增幅HAΔTM/H6N1 gene 33
3-6.1.10 Blunt-end cloning 34
3-6.1.11 重組載體pJET1.2-HAΔTM之轉型作用 (Transformation) 34
3-6.1.12 Colony PCR 34
3-6.1.13 重組載體pJET1.2-HAΔTM之定序 (Sequencing) 35
3-6.1.14 質體pBacPAK8之轉型作用 (Transformation) 35
3-6.1.15 重組載體pJET1.2-HAΔTM與質體pBacPAK8之萃取 35
3-6.1.16 建構重組轉移載體 (Transfer vector) 35
3-6.1.17 重組轉移載體pBacPAK8-HAΔTM之轉型作用 36
3-6.1.18 重組載體pBacPAK8-HAΔTM之確認 36
3-6.1.19 重組載體pBacPAK8-HAΔTM之定序 (Sequencing) 37
3-6.1.20 重組轉移載體pBacPAK8-HAΔTM之大量萃取 37
3-6.2 建構重組桿狀病毒 38
3-6.2.1 共轉移感染 (Co-transfection) 38
3-6.2.2 檢出基因轉殖成功的重組病毒並增殖 (Amplification) 38
3-6.2.3 測定桿狀病毒力價 (50% Tissue Culture Infective Dose, TCID50) 40
3-6.3 rHAΔTM/H6N1蛋白之製備、純化與定量 40
3-6.3.1 Bac-H6抗原盤之免疫螢光染色 (IFA) 40
3-6.3.2 懸浮培養獲取rHAΔTM/H6N1蛋白 41
3-6.3.3 rHAΔTM/H6N1蛋白之濃縮 41
3-6.3.4 rHAΔTM/H6N1蛋白之純化 41
3-6.3.5 rHAΔTM/H6N1蛋白之定量 42
3-6.3.6 rHAΔTM/H6N1蛋白之血球凝集試驗 42
第七節 建立αHA MAbs-based blocking ELISA 42
3-7.1 以indirect ELISA 測試αHA MAbs之特異性及敏感性 42
3-7.2 以direct ELISA測試 Tracer Ab之專一性 43
3-7.3 最佳化αHA MAbs-based blocking ELISA 43
3-7.3.1 最佳化tracer Ab與1209/H5N2或 rHAΔTM/H6N1之比例 43
3-7.3.2 最佳化docking Ab、1209/H5N2或rHAΔTM/H6N1、tracer Ab之比例 44
3-7.4 血清檢體檢測 44
3-7.4.1 血清檢體之血球凝集抑制試驗 (HI test) 44
3-7.4.2 以1209/H5N2 bELISA與rHAΔTM/H6N1 bELISA檢測血清檢體 45
3-7.4.3 1209/H5N2 bELISA與rHAΔTM/H6N1 bELISA之cut-off value、敏感性及特異性分析 45
第四章 結果 47
第一節 抗H5N2與H6N1禽流感病毒血球凝集素之融合瘤單源抗體製備 47
4-1.1 H6N1免疫小鼠之血清力價 47
4-1.2 H5與H6親代融合瘤細胞之篩選 48
第二節 αHA單源抗體之特性鑑定與製備 48
4-2.1 免疫螢光染色 (IFA) 48
4-2.2 血球凝集抑制試驗 (HI test) 49
4-2.3 中和試驗 (Neutralization test) 50
4-2.4 西方墨點法 (Western blot) 51
4-2.5 單源抗體之分型 (Isotyping) 51
4-2.6 單源抗體之純化、定量與酵素標示 (HRP-conjugation) 51
第三節 rHAΔTM/H6N1抗原製備與確認 52
4-3.1 重組rHAΔTM/H6N1基因之選殖 52
4-3.1.1 RT-PCR增幅2838/H6N1 full-length HA gene 52
4-3.1.2 重組載體pJET1.2-HA之確認 52
4-3.1.3 PCR增幅HAΔTM/H6N1 gene 52
4-3.1.4 重組載體pJET1.2- HAΔTM之確認 52
4-3.1.5 重組載體pJET1.2-HAΔTM之定序 53
4-3.1.6 建構重組轉移載體 (Transfer vector) 53
4-3.1.7 重組轉移載體pBacPAK8-HAΔTM之確認 53
4-3.1.8 重組轉移載體pBacPAK8-HAΔTM之定序 53
4-3.1.9 桿狀病毒力價之測定 (50% Tissue Culture Infective Dose, TCID50) 54
4-3.1.10 Bac-H6抗原盤之免疫螢光染色 (IFA) 54
4-3.1.11 rHAΔTM/H6N1 cul. sup. iELISA 54
4-3.1.12 rHAΔTM/H6N1蛋白之濃縮、純化與定量 55
4-3.1.13 rHAΔTM/H6N1 WB 56
4-3.1.14 rHAΔTM/H6N1蛋白之血球凝集試驗 56
第四節 建立αHA MAbs-based blocking ELISA 57
4-4.1 以indirect ELISA測試αHA MAbs之特異性及敏感性 57
4-4.2 以direct ELISA測試 Tracer Ab之專一性 57
4-4.3 最佳化αHA MAbs-based blocking ELISA 58
4-4.4 篩選最佳的抗體組合 (MAbs pairs) 59
4-4.4.1 挑選OD值較高的MAbs pair 59
4-4.4.2 以少量血清檢體篩選最佳抗體組合 59
4-4.4.3 以敏感性及特異性之原理篩選最佳抗體組合 60
4-4.5 血清檢體之檢測 61
4-4.5.1 血清檢體之血球凝集抑制試驗 (HI test) 61
4-4.5.2 1209/H5N2 bELISA與rHAΔTM/H6N1 bELISA之cut-off value、敏感性及特異性分析 61
4-4.5.3 1209/H5N2 bELISA與rHAΔTM/H6N1 bELISA對不同HI titer血清之陽性檢出率 62
第五章 討論 63
第一節 抗體特性鑑定 63
5-1.1 αH5 MAbs特性鑑定 64
5-1.2 αH6 MAbs特性鑑定 67
第二節 rHAΔTM/H6N1蛋白之表現 71
第三節 αHA MAbs-based blocking ELISA之建立與測試 74
5-3.1 篩選最佳抗體組合 74
5-3.2 血清檢測結果之統計分析 76
第六章 結論 80
參考文獻 118
附錄 134


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