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系統識別號 U0026-0607201015230500
論文名稱(中文) 探討修飾過的登革病毒非結構性蛋白1抗體所提供的保護效果
論文名稱(英文) The protective effects provided by antibodies against chimeric dengue virus nonstructural protein 1
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 98
學期 2
出版年 99
研究生(中文) 黃佳慧
研究生(英文) Chia-Hui Huang
學號 S4697407
學位類別 碩士
語文別 英文
論文頁數 65頁
口試委員 指導教授-林以行
口試委員-黎煥耀
口試委員-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 
英文關鍵字 Dengue virus  Nonstructural protein 1  Vaccine development 
學科別分類
中文摘要 受到登革病毒 (DV) 感染的病人臨床症狀包含登革熱、登革出血熱、和登革休克症等,而血小板數低下、凝血機制異常或血管內皮細胞遭受到破壞,都可能是造成出血的原因。實驗室先前的研究指出,抗DV非結構蛋白1 (NS1) 抗體會和人類的內皮細胞及血小板產生交互作用,導致內皮細胞走向凋亡、血小板凝血機制異常,以及在小鼠主動免疫的實驗中發現,有延長小鼠出血時間的趨勢。利用蛋白質體學及序列比對分析的方式發現,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。以安全性來考量疫苗的發展,我們將具有交互作用的抗原決定位進行切除,產生了含有DV NS1 N端胺基酸1-270與JEV NS1 C端胺基酸271-352的NS1嵌合蛋白,被命名為DJ NS1。實驗顯示DJ NS1抗體對人類內皮細胞及血小板的黏附能力較全長DV NS1抗體低,在小鼠模式中也發現,給予DV NS1主動免疫的小鼠有出血時間延長的趨勢,而DJ NS1主動免疫則不會造成相同的情形。另一方面,利用DV誘發小鼠出血的實驗模式,探討被動給予DJ NS1抗體是否可以提供保護能力,發現被動給予DJ NS1抗體可以減緩DV感染後造成出血時間延長的現象,以及降低在感染DV的局部皮膚上所造成出血的情形。KU812巨大細胞為DV的標的細胞之一,在缺乏抗體的促進作用之下,仍可以順利地被DV所感染。DJ NS1抗體可誘使被DV感染的KU812細胞走向細胞凋亡,同時,會抑制被DV感染的KU812細胞釋放MIP-1 alpha及MIP-1 beta 的能力。綜合以上的發現,DJ NS1可提供作為登革疫苗研發的新策略。
英文摘要 Patients infected by dengue viruses (DV) may display dengue fever, dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Hemorrhagic syndromes of DHF/DSS include thrombocytopenia, coagulopathy and vasculopathy, which are related with dysfunction of endothelial cells and platelets. Previous studies in our laboratory showed that antibodies (Abs) against DV nonstructural protein 1 (NS1) cross-react with human endothelial cells and induce apoptosis. Platelet dysfunction and bleeding tendency are also induced by anti-DV NS1 Abs. Using sequence homology analysis, we found that the C-terminal region of DV NS1 protein contains cross-reactive epitopes shared with self-antigens. For safety in vaccine development, the cross-reactive epitopes of DV NS1 protein should be deleted or modified. We have generated the chimeric NS1 protein, which consists of N-terminal DV NS1 (a.a. 1-270) and C-terminal JEV NS1 (a.a. 271-352) (designated DJ NS1). The anti-DJ NS1 Abs showed lower binding activity to human endothelial cells and platelets than that of anti-DV NS1 Abs. In the murine model, DV NS1 immunization caused prolonged bleeding time, but DJ NS1 immunization did not. Passive immunization with anti-DV NS1 or anti-DJ NS1 Abs could reduce DV-induced prolonged bleeding time and hemorrhage on the local skin. KU812 basophil/mast cell line was susceptible to DV infection without enhancing Abs. Anti-DJ NS1 Abs induced DV-infected KU812 cells to undergo apoptosis. Moreover, the expression of MIP-1 alpha and MIP-1 beta in DV-infected KU812 cells was also reduced by anti-DJ NS1 Abs. According to these findings, DJ NS1 may provide a strategy for dengue vaccine development.
論文目次 Chinese Abstract I
English Abstract II
Acknowledgement III
Contents IV
Figure List VI
Abbreviation List VII
Introduction 1
Objective and Experimental Design 11
1. To confirm the absence of pathogenic effect of Abs against DJ NS1 protein lacking cross-reactive epitopes both in vitro and in vivo 12
2. To evaluate the protective effects provided by anti-DJ Abs in DV-induced hemorrhagic mouse model 12
3. To investigate the effects of anti-DJ Abs in DV-infected KU812 cells 13
Materials and Methods 14
A. Materials 14
A-1 Mice 14
A-2 Cell lines 14
A-3 Platelet preparation 14
A-4 Virus 15
A-5 Preparation of recombinant proteins and antibodies 15
A-6 Drugs 15
A-7 Antibodies 17
A-8 Consumables 18
A-9 Instruments 19
B. Methods 20
B-1 Cell culture 20
B-2 Virus culture 20
B-3 Plaque assay 21
B-4 Antibody titer determination 21
B-5 Western blot analysis 21
B-6 Platelet and endothelial cell binding assay 22
B-7 Bleeding time and platelet count 22
B-8 Animal protection model 22
B-9 Histopathology 23
B-10 Immunohistochemistry staining 23
B-11 Dengue virus infection of KU812 cells 23
B-12 Detection of infection rate 24
B-13 Analysis of apoptosis 24
B-14 Determination of lactate dehydrogenase (LDH) activity 24
B-15 ELISA of cytokine and chemokine levels 24
B-16 Statistics 25
Results 26
1. To confirm the absence of pathogenic effect of Abs against chimeric NS1 protein lacking cross-reactive epitopes both in vitro and in vivo 26
2. To evaluate the protective effects provided by anti-DJ NS1 Abs in DV-induced hemorrhagic mouse model 28
3. To investigate the effects of anti-DJ NS1 Abs in DV-infected KU812 cells 29
Discussion 32
References 40
Figures 49
Curriculum vitae 65
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