系統識別號 U0026-2207201415491200
論文名稱(中文) 探討登革病毒非結構性蛋白1誘發之抗體對血纖溶酶原活化之影響
論文名稱(英文) Study on the effects of dengue virus nonstructural protein 1-induced antibodies on plasminogen activation
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 102
學期 2
出版年 103
研究生(中文) 林怡君
研究生(英文) Jessica Lin
學號 T36014084
學位類別 碩士
語文別 英文
論文頁數 82頁
口試委員 指導教授-葉才明
口試委員-Robert Anderson
中文關鍵字 登革病毒  非結構性蛋白1  血纖溶酶原  自體抗體 
英文關鍵字 Dengue virus  Nonstructural protein 1  Plasminogen  Autoantibody 
中文摘要 登革病毒(Dengue virus)是一種藉由蚊子叮咬傳播的病毒,其感染人類除了造成典型的登革熱(dengue fever)外,也可能引起較嚴重且可致死的登革出血熱(dengue hemorrhagic fever, DHF)或登革休克症候群(dengue shock syndrome, DSS)。DHF/DSS其中一個病徵是患者的凝血(coagulation)及纖溶(fibrinolysis)功能發生失衡,導致異常出血。但DHF/DSS發生出血的機制目前仍未完全瞭解。登革病毒非結構性蛋白1(nonstructural protein 1, NS1)在感染早期就會出現於患者的血液中,並且可能透過分子相似性(molecular mimicry)造成疾病。我們先前的研究發現登革病人血清中存有抗凝血酶(thrombin)的抗體,這些抗體會辨認到登革病毒的NS1,並且同時具有抑制凝血及促進纖溶的活性。為了進一步探討NS1是否確實會誘發宿主產生和凝血相關因子交叉反應的抗體,本篇研究我們以登革病毒重組NS1免疫小鼠及兔子,實驗結果顯示NS1免疫的小鼠及兔子血清中會出現與凝血酶及血纖溶酶原(plasminogen, Plg)交叉反應的抗體。為了進一步探討這些抗體對凝血及纖溶的影響,我們製備了會和Plg交叉反應的抗NS1的單株抗體,並且發現其中幾株單株抗體具有絲胺酸蛋白酶(serine protease)活性,可促進Plg活化成纖溶酶(plasmin)。此外,抗原決定位定位(epitope mapping)分析顯示其中一株單株抗體2A5會辨認NS1 C端305-311胺基酸殘基 (residue),並且可能與Plg上609-616胺基酸殘基交叉反應。總結以上結果,本篇研究發現登革病毒NS1誘發產生之抗體與Plg交叉反應可能促進Plg活化成纖溶酶造成纖溶亢進(hyper-fibrinolysis)。在NS1疫苗的設計上應避開這些可能誘發自體抗體產生的區域,避免造成凝血相關副作用。
英文摘要 Dengue virus (DENV) is a mosquito-transmitted virus, which infects humans might cause flu-like illness called dengue fever (DF) or lead to potentially lethal diseases like dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Abnormal activation of the coagulation and fibrinolysis system is one of the hallmarks associated with DHF/DSS patients. However, the mechanism to cause hemorrhage in DHF/DSS is still not fully understood. DENV nonstructural protein 1 (NS1) is secreted early during infection and is believed to be involved in DENV pathogenesis through molecular mimicry. In previous study, we found anti-thrombin antibodies in dengue patients, which can recognize NS1, contain both anti-thrombotic and pro-fibrinolytic activities. However, it is unclear whether these antibodies are indeed induced by DENV NS1. Thus, we immunized both mice and rabbits with recombinant NS1 to test whether NS1 can induce coagulation factor-cross-reactive antibodies. Results from both NS1 hyper-immunized mice and rabbits sera indicated the presence of antibodies that can bind to thrombin and plasminogen (Plg). To study the effects of these NS1-induced autoantibodies on coagulation and fibrinolysis, we generated several Plg cross-reactive anti-NS1 monoclonal antibodies (mAbs) and found some of these mAbs were endowed with serine protease activity and could enhance Plg conversion to plasmin. In addition, the results of epitope mapping revealed that mAb 2A5 could recognize NS1 C-terminal residues 305-311 and probably cross-react with Plg on region 609-616. Taken together, these results suggest that DENV NS1-induced antibodies cross-react with Plg may enhance Plg conversion to plasmin and contribute to hyper-fibrinolysis. In vaccine design, the epitopes recognized by these NS1-induced Plg cross-reactive autoantibodies should be avoided to prevent possible side effects.
論文目次 Abstract (Chinese) I
Abstract II
Acknowledgement IV
Table of Contents V
List of Tables VIII
List of Figures IX
Abbreviations Index XI
1. Introduction 1
1.1. Dengue virus 1
1.1.1. Epidemiology of dengue virus infection 1
1.1.2. Characteristics of dengue virus 2
1.1.3. Clinical symptoms and diagnostic methods of DENV infection 6
1.1.4. Hypotheses on the pathogenesis of DHF/DSS 8
1.2. Abnormal coagulation in dengue patients 11
1.2.1. Hemostatic system 11
1.2.2. Laboratory findings in dengue patients 12
1.2.3. Molecular mimicry between DENV and coagulation factors 13
2. Objective and Specific Aims 15
3. Materials and Methods 17
3.1. Materials 17
3.1.1. Mice 17
3.1.2. Virus 17
3.1.3. Cell lines 17
3.1.4. Proteins 17
3.1.5. Synthetic peptides 18
3.1.6. Reagents 18
3.1.7. Antibodies 21
3.1.8. Consumables 21
3.1.9. Instruments 22
3.2. Methods 23
3.2.1. SDS-PAGE 23
3.2.2. Western blot 24
3.2.3. Mouse immunization 24
3.2.4. ELISA 25
3.2.5. Cell culture 25
3.2.6. Production of monoclonal antibodies 26
3.2.7. Isotyping and purification of monoclonal antibodies 28
3.2.8. Virus culture 28
3.2.9. Fluorescent focus assay 28
3.2.10. Indirect immunofluorescence assay 29
3.2.11. Sequence alignment and structure modeling 30
3.2.12. Chromogenic assay of plasminogen activation and serine protease activity 30
3.2.13. Plasmin formation assay 31
3.2.14. Epitope mapping using phage-displayed random peptide library 31
3.2.15. Phage ELISA 32
3.2.16. Statistical analysis 33
4. Results 34
4.1. DENV2 NS1 immunization 34
4.2. Determination of the presence of coagulation factor-cross-reactive antibodies in the immune sera 34
4.3. Production and characterization of Plg cross-reactive anti-NS1 mAb 35
4.4. The effects of Plg cross-reactive anti-NS1 mAbs on Plg activation 36
4.5. Determination of the serine protease activity of Plg cross-reactive anti-NS1 mAbs 37
4.6. Epitope mapping of Plg cross-reactive anti-NS1 mAb 2A5 37
4.7. Analysis of the putative epitope recognized by mAb 2A5 38
4.8. Epitope mapping of Plg non-cross-reactive anti-NS1 mAb 2E8 39
4.9. Confirmation of epitopes recognized by mAbs 2A5 and 2E8 by synthetic peptides 39
5. Discussion 41
6. Conclusion 47
7. References 48
8. Tables 62
9. Figures 64
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