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系統識別號 U0026-1208201112231700
論文名稱(中文) 探討修飾過的登革病毒非結構性蛋白1抗體在體外及主動免疫小鼠模式之保護效果
論文名稱(英文) Study on the protective effects of chimeric dengue virus nonstructural protein 1 antibodies both in vitro and in active immunization mouse model
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 99
學期 2
出版年 100
研究生(中文) 周琬軒
研究生(英文) Wan-Shan Chou
學號 s46984078
學位類別 碩士
語文別 英文
論文頁數 80頁
口試委員 指導教授-林以行
口試委員-黎煥耀
召集委員-林秋烽
口試委員-羅伯安德森
中文關鍵字 登革病毒  非結構性蛋白1  疫苗的發展  小鼠模式 
英文關鍵字 Dengue virus  Nonstructural protein 1  Vaccine development  Mouse model 
學科別分類
中文摘要 登革病毒(DV) 感染所造成的臨床症狀包括較輕微的登革熱乃至嚴重的登革出血熱和登革休克症,在病人身上可以觀察到血小板低下、凝血機制異常或血管內皮細胞遭受到破壞,都是造成出血的可能原因。實驗室先前研究證實,辨識DV非結構蛋白1 (NS1) 之抗體會與人類的內皮細胞及血小板產生交互作用,促使內皮細胞進行細胞凋亡並使血小板凝集機制異常。蛋白質體學及蛋白質序列分析比對的結果顯示NS1蛋白質C端的胺基酸與內皮細胞上標的蛋白質的序列非常相似。考量以NS1為疫苗發展的安全性,我們將具有交互作用的抗原決定位去除,產生了含有DV NS1 N端胺基酸1-270與日本腦炎病毒(JEV) NS1 C端胺基酸271-352的NS1嵌合蛋白,並命名為DJ NS1。先前研究證實DJ NS1抗體對人類內皮細胞及血小板的結合能力較全長DV NS1抗體低,以DV NS1主動免疫的小鼠有出血時間延長的趨勢,但DJ NS1則不會造成類似的結果。在DV引起小鼠出血的模式中,發現被動給予DJ NS1抗體可以減緩DV感染所造成出血時間延長的現象,並降低DV感染在局部皮膚上造成的出血情形,證實抗DJ NS1抗體具保護小鼠對抗DV感染之效果。本實驗架構一主動免疫小鼠的模式,發現給予小鼠DJ NS1配合鋁鹽作為佐劑,四次接種後可引起小鼠體內高效價的抗體反應,使用高分子型奈米複合物作為佐劑時,三次接種即可引起小鼠體內明顯的抗體反應。為建立以stat-1基因剔除 (stat-1-/-)小鼠感染DV引起小鼠出血的模式,並進一步研究DJ NS1主動免疫對抗DV感染之保護性,我們先行測試stat-1-/-小鼠在DV引起小鼠出血的模式中所需的感染劑量。實驗證明使用9 ׬¬¬ 106 PFU/mouse的病毒,即可引起stat-1-/-小鼠出血,並造成小鼠出血時間的延長。細胞實驗的結果顯示,DV能夠感染表現DC-SIGN的THP-1人類單核球細胞以及HMEC-1人類內皮細胞。DV感染會促使表現DC-SIGN的THP-1細胞表現IL-8而給予抗DJ NS1抗體可抑制此現象,進一步發現抗DJ NS1抗體可引起被DV感染的HMEC-1細胞死亡。綜合以上結果,此研究證明抗DJ NS1抗體對於被DV感染的細胞提供了保護力,此外,本研究也提供了登革疫苗發展所需的重要資訊。
英文摘要 Dengue virus (DV) infection may cause dengue fever or severe dengue hemorrhagic fever and dengue shock syndrome, yet the pathogenic mechanisms remain unresolved. We previously found that antibodies (Abs) against DV nonstructural protein 1 (NS1) may cross-react with human endothelial cells and platelets, and cause their dysfunctions. Results of sequence homology analysis showed that the C-terminal region of DV NS1 protein contains cross-reactive epitopes sharing with self-antigens. For safety concern of vaccine development, the cross-reactive epitopes of DV NS1 protein should be deleted or modified. We have constructed a recombinant NS1 protein, in which the DV NS1 C-terminal a.a. 271 to 352 is replaced with JEV NS1 (designated DJ NS1). The anti-DJ NS1 Abs showed lower binding activity with human platelets and endothelial cells than that of anti-DV NS1 Abs. Active immunization with DV NS1 induced prolonged mouse tail bleeding time, but DJ NS1 immunization did not cause a similar effect. Passive immunization with anti-DJ NS1 Abs in DV-infected mice could reduce DV-induced prolonged bleeding time and hemorrhage on the local subcutaneous tissues. In the present study, we have established an active immunization model. Using alum as adjuvant, mice immunized with DJ NS1 proteins for four times could induce robust Abs response. While using polymer-based nanocomplex as adjuvant, three inoculations were sufficient to induce Abs response in mice. To verify the protective effects in DV-infected mouse model using stat-1 knockout (stat-1-/-) mice, we first examined the infection dose and found that 9 ׬¬¬ 106 PFU/mouse of DV could cause pathogenic effects in stat-1-/- mice. In vitro study suggested that both THP-1 monocytes and HMEC-1 endothelial cells were susceptible to DV infection. DV-infected DC-SIGN-transgenic THP-1 cells showed increased level of IL-8 production, which was reduced by anti-DJ NS1 Abs treatment. We also found that anti-DJ NS1 Abs could induce DV-infected HMEC-1 cell death. Taken together, this study shows the protective effect of anti-DJ NS1 Abs on DV-infected cells, and provides important information for strategies of vaccine development.
論文目次 Abstract in Chinese I
Abstract in English III
Acknowledgement V
Contents VI
Table List X
Figure List XI
Abbreviations XII
Introduction 1
Objective and Experimental Design 16
1. To establish an active immunization mouse model that can induce robust antibody response against chimeric DJ NS1 protein. 17
2. To test a DV-induced hemorrhage model using stat-1-/- mice. 18
3. To investigate the effects of anti-DJ Abs in DV-infected DC-SIGN-transgenic THP-1 cells (DC-SIGN THP-1) and HMEC-1 cells. 18
Materials and Methods 20
A. Materials 20
A-1 Mice 20
A-2 Cell lines 20
A-3 Virus 20
A-4 Preparation of recombinant proteins and antibodies 21
A-5 Preparation of polymer-based nanocomplex and nanogold-based nanocomplex 21
A-6 Drugs 22
A-7 Antibodies 24
A-8 Consumables 24
A-9 Instruments 25
B. Methods 26
B-1 Cell culture 26
B-2 Virus culture 27
B-3 Plaque assay 27
B-4 Antibody titer determination 27
B-5 Active immunization mouse model 28
B-6 Antigen-adjuvant preparation 28
B-7 Bleeding time and platelet count 28
B-8 DV-induced hemorrhage mouse model 29
B-9 Histopathology 29
B-10 Detection of DC-SIGN expression on THP-1 cells 29
B-11 Dengue virus infection of DC-SIGN THP-1 cells 30
B-12 Dengue virus infection of HMEC-1 cells 30
B-13 Detection of infection rate 30
B-14 Detection of anti-NS1 Abs binding activity on DV-infected cells 30
B-15 ELISA of cytokine levels 31
B-16 Determination of lactate dehydrogenase (LDH) activity 31
B-17 Statistics 31
Results 32
1. To establish an active immunization mouse model that can induce robust antibody response against chimeric DJ NS1 protein. 32
1.1 To prepare the DV NS1, JEV NS1 and DJ NS1 proteins. 32
1.2 Active immunization with NS1 proteins in Freund’s adjuvant for four times can induce robust Abs responses in mice. 32
1.3 Active immunization with NS1 proteins in alum for different times to determine the Abs responses in mice. 33
1.4 Active immunization with DV NS1 but not DJ NS1 causes prolonged bleeding time in mice. 33
1.5 Active immunization with NS1 proteins in different adjuvants for different times to determine the adjuvant activity. 34
2. To test a DV-induced hemorrhage model using stat-1-/- mice. 35
2.1 Infection of stat-1-/- mice with a virus dosage of 9 × 106 PFU/mouse for 3 or 4 days both could induce prolonged bleeding time. 35
2.2 Infection of stat-1-/- mice with a virus dosage of 9 × 106 PFU/mouse for 3 or 4 days both could induce hemorrhage and spleen enlargement. 35
3. To investigate the effects of anti-DJ Abs in DV-infected DC-SIGN-transgenic THP-1 cells and HMEC-1 cells. 36
3.1 To confirm the DC-SIGN expression in DC-SIGN-transgenic THP-1 cells. 36
3.2 Both DC-SIGN THP-1 cells and HMEC-1 cells are susceptible to DV infection. 36
3.3 Anti-DV NS1 and anti-DJ NS1 Abs show binding activity to DV-infected DC-SIGN THP-1 and HMEC-1 cells. 37
3.4 Anti-DJ NS1 Abs reduce IL-8 expression in DV-infected DC-SIGN THP-1 cells. 37
3.5 Anti-DJ NS1 Abs induce DV-infected HMEC-1 cell death. 38
Discussion 39
References 47
Tables 58
Figures 61
Appendix 74
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