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系統識別號 U0026-0708201317412300
論文名稱(中文) 利用單鏈抗體尋找對登革病毒具中和能力抗體所辨識的抗原決定位
論文名稱(英文) Identification of protective epitopes against dengue virus using single chain fragment of variable region technique
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 101
學期 2
出版年 102
研究生(中文) 邱千玳
研究生(英文) Cian-Dai Ciou
學號 t36001099
學位類別 碩士
語文別 中文
論文頁數 102頁
口試委員 指導教授-葉才明
口試委員-王淑鶯
口試委員-林振文
中文關鍵字 中和抗體  單鏈抗體  噬菌體表現系統 
英文關鍵字 neutralization  single chain fragment of variable region  phage display 
學科別分類
中文摘要 登革病毒主要分布在熱帶及亞熱帶地區,並且分為四種血清型,全球約有將近一半的人口都在登革病毒分布範圍內。登革病毒是藉由埃及斑蚊或白線斑蚊作為病媒蚊叮咬所感染,感染登革病毒產生的症狀則分為較輕微的登革熱或較為嚴重的登革出血熱及登革休克症候群。目前市面上還並未有針對四種血清型的病毒所開發出的疫苗或者作為治療的藥物。而登革病毒感染所造成的嚴重症狀可能的原因之一為抗體依賴性增強作用,由於初次感染登革病毒所產生出來的抗體雖然有能力辨認到另外三型血清型的抗體,但卻未有中和病毒能力,反而藉由Fc 接受器,讓單核球或巨噬細胞將結合上病毒的抗體胞吞到細胞中,讓病毒在細胞中複製,造成更嚴重的症狀。為了篩選出具有中和病毒能力的抗體,我們比較文獻上常用來產生對抗登革病毒的幾種登革病毒蛋白作為抗原,分別為聚乙二醇沉澱的登革病毒顆粒、登革病毒RNA、登革病毒外套膜第三區重組蛋白或登革病毒非結構性蛋白一之重組蛋白,比較這些登革病毒蛋白作為抗原免疫出來的小鼠所產生出的血清中和病毒的能力。聚乙二醇沉澱的為成熟的登革病毒顆粒,登革病毒外套膜第三區蛋白在文獻上被認為是被宿主辨認後具有產生中和抗體的一段區域,而登革病毒非結構性蛋白一則被發現免疫後產生出的抗體並不會產生抗體依賴性增強作用。實驗結果發現以聚乙二醇沉澱的登革病毒顆粒來免疫小鼠所得到的血清中具有最強的中和登革病毒能力。我們利用聚乙二醇沉澱的登革病毒顆粒免疫的小鼠篩選出具有中和登革病毒能力的抗體,而為了避免掉抗體依賴性增強作用的影響,以噬菌體表現系統來表現帶有輕鏈和重鏈變異區的抗原決定區單鏈抗體。經過五次與登革病毒進行的親和性篩選之後,以酵素連結免疫吸附分析來篩選出對登革病毒具有高親和性的單株單鏈抗體,並且再進一步篩選出具有中和登革病毒的單鏈抗體,為了得到大量的單鏈抗體,我們利用大腸桿菌HB2151來表現單鏈抗體,再以流式細胞儀分析這些單鏈抗體中和登革病毒能力。最後篩選出三株具有中和登革病毒能力的單鏈抗體25、37、39,其中單鏈抗體25進一步利用帶有隨機胜肽片段的噬菌體與單鏈抗體進行親和性篩選,藉而分析單鏈抗體所辨認到的抗原決定位。我們發現從登革病毒感染的病人血清中具有辨認到這段抗原決定位序列的抗體,便將這段序列再次免疫小鼠,結果顯示其小鼠血清中抗體仍保有辨認到登革病毒的能力,並且具有中和登革病毒的能力。
英文摘要 Dengue virus (DENV) is mainly found in tropical and subtropical regions, and divided into four serotypes. Dengue virus infection causes mild dengue fever and potentially fatal dengue hemorrhagic fever (DHF)/ dengue shock syndrome (DSS), which is transmitted by the mosquito Aedes aegypti. Currently, there are no approved vaccines or antiviral therapies against four serotypes of DENV infections, and only fluid replacement is available for clinical treatment. Antibody-dependent enhancement (ADE) has been proposed as a mechanism for increased disease severity during secondary DENV infection. According to ADE, antibodies induced in previous infection can enhance DENV infection in monocytes/macrophages through Fc receptor. To develop vaccine candidates against DENV, we immunized BALB/c mice with different DENV proteins, such as PEG-precipitated-DENV particle, DENV RNA, recombinant DENV envelope protein domain III or recombinant DENV NS1, and compared the neutralizing ability of immune serum. Sera from PEG-precipitated-DENV particle immunized mice showed the best neutralizing ability against DENV infection than sera from other DENV proteins-immunized mice. To avoid ADE effect, we used phage display to generate single chain fragment of variable region (scFv) from PEG-precipitated DENV-immunized mice to further study their protective effects against DENV. After five times of panning, anti-DENV scFv phages were selected by ELISA to test their binding ability against DENV. In addition, anti-DENV scFv proteins were expressed from E.coli strain HB2151 and purified by nickel column. Some of them showed significantly neutralizing abilities against DENV infection by flow cytometry. Three potential DENV neutralizing scFv proteins 25, 37 and 39 were selected. The epitope of scFv recognized were identified by phage display random peptide library. We found that dengue patients’ sera can recognize the epitope of scFv 25. Furthur more, we immunized BALB/c mice with peptide of scFv 25 epitope.The results showed that mice sera can recogniz DENV as well as the epitope of scFv 25. Besides, immunized mice sera significantly inhibited DENV replication. Our data suggested that anti-DENV scFv 25 could be used as an anti-viral drug or diagnostic tool.
論文目次 中文摘要 I
Abstract III
致謝 V
總目錄 VI
表目錄 IX
圖目錄 X
縮寫指引 XIII
1. 緒論 1
1.1. 登革病毒 1
1.1.1. 登革病毒緒論 1
1.1.2. 登革病毒感染現況 4
1.1.3. 登革病毒感染的臨床病徵及診斷 4
1.1.4. 登革病毒致病機制 6
1.1.5. 抗體依賴性增強作用 7
1.1.6. 登革病毒疫苗及藥物發展 8
1.2. 以噬菌體(phage)表現技術之單鏈抗體 (single chain fragment of variable region, scFv) 9
1.2.1. 噬菌體 9
1.2.1.1. 噬菌體概論 9
1.2.1.2. 噬菌體結構 9
1.2.1.3. 噬菌體的生命週期 10
1.2.2. 噬菌體表現的發展 11
1.2.2.1. 噬菌體表現系統的種類 11
1.2.2.2. 噬菌體表現系統的應用 13
1.2.3. 單鏈抗體發展及應用 14
2. 實驗動機與目標 16
3. 實驗方法與材料 18
3.1. 登革病毒之製備 18
3.1.1. 登革病毒之培養 18
3.1.2. 登革病毒效價之定量 18
3.1.3. 登革病毒RNA之萃取 18
3.2. 小鼠免疫 19
3.2.1. 小鼠品系與來源 19
3.2.2. PEG沉澱登革病毒顆粒及重組蛋白免疫小鼠之前處理 19
3.2.3. RNA免疫小鼠之前處理 20
3.2.4. 合成胜肽免疫小鼠之前處理 20
3.2.5. 免疫小鼠之技術和流程 21
3.2.6. 免疫小鼠血清的製備 22
3.2.7. 血清抗體效價的測定 22
3.2.8. 血清抗體中和病毒能力測定 23
3.3. 噬菌體表現技術製造對抗登革病毒的單鏈抗體 24
3.3.1. 構築單鏈抗體基因庫 24
3.3.1.1. 萃取免疫小鼠脾臟RNA及反轉錄cDNA 24
3.3.1.2. 抗體變異區基因之純化 25
3.3.1.3. 單鏈抗體基因庫之製造 27
3.3.1.4. 單鏈抗體基因庫與噬菌體質體(phagemid)之接合 28
3.3.1.5. 輔助噬菌體(helper phage)之製備 30
3.3.1.6. 單鏈抗體表現之噬菌體庫之製造 31
3.3.2. 篩選特異性單鏈抗體 32
3.3.2.1. 特異性單鏈抗體之生物篩選(bio-panning) 32
3.3.2.2. 特異性單鏈抗體表現之單一噬菌體之篩選 34
3.4. 單鏈抗體重組蛋白 35
3.4.1. 單鏈抗體重組蛋白的表現及純化 35
3.4.2. 單鏈抗體重組蛋白結合能力之確認 36
3.4.3. 單鏈抗體重組蛋白中和登革病毒的能力測試 37
3.5. 單鏈抗體定序及序列比對 38
3.6. 預測單鏈抗體辨識之抗原決定位 38
3.6.1. 噬菌體效價測試 38
3.6.2. 噬菌體胜肽庫之結合篩選 39
3.6.3. 噬菌體結合能力測試 40
3.6.4. 噬菌體單股DNA之萃取 41
4. 結果 43
4.1. 免疫小鼠及製造中和登革病毒的血清抗體 43
4.1.1. 登革病毒抗原製備 43
4.1.2. 以不同登革病毒抗原免疫小鼠之血清效價分析 43
4.1.3. 以不同登革病毒抗原免疫小鼠之血清中和登革病毒能力 43
4.2. 登革病毒單鏈抗體製備 44
4.2.1. 從免疫小鼠脾臟抗體基因庫構築單鏈抗體 44
4.2.2. 登革病毒特異性單鏈抗體生物親和性篩選 45
4.2.3. 登革病毒特異性單鏈抗體結合能力 45
4.2.4. 登革病毒特異性單鏈抗體中和登革病毒能力 45
4.3. 登革病毒單鏈抗體分析 46
4.3.1. 登革病毒單鏈抗體序列分析 46
4.3.2. 登革病毒單鏈抗體基因分析 46
4.4. 登革病毒單鏈抗體抗原決定位分析 46
4.5. 以單鏈抗體之抗原決定位(LTQAYRD)免疫小鼠 47
4.5.1. LTQAYRD免疫小鼠之血清效價分析 47
4.5.2. LTQAYRD免疫小鼠之血清辨認登革病毒能力 47
4.5.3. LTQAYRD免疫小鼠之血清中和登革病毒能力 48
5. 討論 49
5.1. 不同登革病毒抗原免疫的抗原反應 49
5.2 中和登革病毒單鏈抗體的應用 50
5.3 單鏈抗體之抗原決定位 51
6. 結論 53
7. 參考文獻 54
8. 表附錄 67
9. 圖附錄 70
附錄一、 試劑配方 94
附錄二、試劑及實驗耗材和抗體 98
附錄三、儀器 102
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