系統識別號 U0026-0812200915110323
論文名稱(中文) 登革病毒缺乏交叉反應的非結構蛋白1抗體提供保護作用之評估
論文名稱(英文) Evaluation of protective effects provided by antibodies against dengue virus nonstructural protein 1 lacking cross-reactive epitopes
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 97
學期 2
出版年 98
研究生(中文) 盧怡恬
研究生(英文) Yi-Tien Lu
電子信箱 s4696107@mail.ncku.edu.tw
學號 s4696107
學位類別 碩士
語文別 英文
論文頁數 62頁
口試委員 指導教授-林以行
中文關鍵字 自噬現象  非結構蛋白1  登革病毒 
英文關鍵字 nonstructural protein 1  autophagy  dengue virus 
中文摘要 登革病毒感染造成的症狀由輕微登革熱,乃至於可能會致死的登革出血熱或登革休克症狀。研究顯示,多種致病機制參與在登革病毒所引發的登革出血熱或登革休克症狀,其中包括抗體依賴性增強作用,以及宿主對抗病毒所產生的不適當免疫反應。先前的研究顯示,當登革病毒感染人類肝細胞株以及單核球細胞會誘使自噬現象的發生,並有助於病毒的複製。在致病機制上,登革病毒也會利用抗體依賴性增強作用感染巨大細胞,利用電子顯微鏡觀察在被感染細胞內有自噬體的形成,而且有增強抗體的組別可偵測到較高量的自噬體。本研究亦發現在被感染的巨大細胞內,LC3-II與LC3-I的比例會上升。再者,無論有無增強抗體的存在下,當給予自噬現象抑制劑3-MA,病毒的感染率均會下降。此外實驗室先前研究發現,抗非結構蛋白1 (NS1) 抗體會與血小板及內皮細胞發生交叉反應,藉由序列比對分析發現NS1蛋白質N端及C端與標的蛋白質有交叉作用的抗原決定位。本研究我們利用動物模式以及細胞培養方式,評估在登革病毒感染下,全長NS1蛋白質、delta C NS1 (切除胺基酸C端序列271-352) 以及delta NC NS1 (切除胺基酸N端序列1-35與C端271-352) 的保護效果。實驗顯示抗delta NC NS1抗體對血小板和內皮細胞的結合能力低於抗全長NS1抗體與抗delta C NS1抗體。研究結果顯示,抗全長NS1、抗delta C NS1、以及抗delta NC NS1抗體會引發被登革病毒感染的巨大細胞凋亡。在小鼠模式中可觀察到以全長NS1蛋白質主動免疫小鼠後,會延長小鼠的出血時間,但delta C NS1與delta NC NS1免疫之小鼠則不會有此病理現象發生。被動免疫小鼠實驗顯示,抗delta C NS1抗體及抗delta C NS1抗體與抗全長NS1抗體比較,有較低的結合至血小板上的能力。日後擬將針對抗全長NS1抗體以及抗其他重組NS1蛋白抗體,對於登革病毒所誘使的細胞自噬現象、細胞凋亡以及病毒複製進一步探討。本研究有助於瞭解delta C NS1與delta NC NS1抗體在登革病毒感染可能提供的保護效果。
英文摘要 Dengue virus (DV) infection causes diseases ranging from mild dengue fever to life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Several mechanisms are suggested to be involved in the pathogenesis of DHF/DSS progression, including antibody-dependent enhancement (ADE) and abnormal host immune responses. Recent reports have demonstrated DV induced autophagy in human hepatoma cell lines and peripheral blood monocytes which promote viral replication. Mast cells are susceptible to ADE-mediated DV infection. We have also detected autophagosome vesicles in DV-infected mast cells under transmission electron microscopy. In the presence of DV-enhancing antibodies, there were higher amounts of autophagosomes in each infected cell than in cells infected with DV without enhancing antibodies. Our results also showed an increase of the LC3-II/LC3-I ratio in DV-infected mast cells. The percentages of DV-infected cells, with or without enhancing antibodies, were reduced by the autophagy inhibitor 3-MA. In addition, our previous studies showed that antibodies against DV nonstructural protein 1 (NS1) cross-reacted with human platelets and endothelial cells. Based on the sequence analysis, the N- and C-terminal regions of DV NS1 possess cross-reactive epitopes which are shared between NS1 and self-antigens. We compared the effects of NS1,delta C NS1 (deletion of amino acids 271-352) and delta NC NS1 (deletion of amino acids 1-35 and 271-352) in DV infection using animal models and cell cultures. Results showed that the binding activity of delta NC NS1 antibodies to endothelial cells and platelets was lower than those of NS1 and delta C NS1 antibodies. We found that these three antibodies all induced DV-infected cell apoptosis. In the murine model, NS1 immunization caused prolonged bleeding time, while delta C NS1 and delta NC NS1 immunization did not cause a similar effect. In a passive immunization model, the binding abilities of anti-delta C NS1 and anti-delta NC NS1 antibodies to platelets were much lower than that of anti-DV NS1 antibodies. The effects of antibodies against NS1 or truncated NS1 on DV-induced autophagy, apoptosis, and viral replication require further investigation. This study offers insights into the potential protective effects provided by delta C NS1 and delta NC NS1 antibodies in DV infection.
論文目次 Chinese Abstract I
English Abstract II
Acknowledgement IV
Contents V
Figure List VII
Abbreviation List VIII
Introduction 1
Objective and Experimental Design 12
1. To investigate the fate of mast cells after DV infection. 12
2. To compare the effects of NS1, delta C NS1 and delta NC NS1 in DV infection using animal models and cell cultures. 13
Materials and Methods 15
A. Materials 15
A-1 Mice 15
A-2 Cell lines 15
A-3 Platelet preparation 15
A-4 Virus 15
A-5 Dengue patient sera 16
A-6 Recombinant proteins and antibodies preparation 16
A-7 Drugs 16
A-8 Antibodies 18
A-9 Consumables 19
A-10 Instruments 19
B. Methods 20
B-1 Cell culture 20
B-2 Virus culture 21
B-3 Plaque assay 21
B-4 Dengue virus infection 22
B-5 Detection of infection rate 22
B-6 Analysis of apoptosis 22
B-7 Transmission electron microscopy 22
B-8 Western blot analysis 23
B-9 Platelet and endothelial cell binding assay 23
B-10 Bleeding time and platelet count 23
B-11 Statistics 24
Results 25
1. Dengue virus infection induces autophagy in mast cells. 25
2. Comparing the effects of NS1, delta C NS1 and delta NC NS1 in DV infection using animal models and cell cultures. 27
Discussion 31
References 38
Figures 47
Appendix 60
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