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系統識別號 U0026-2808201412385200
論文名稱(中文) 以小鼠及擬人化小鼠模式探討抗登革病毒非結構性蛋白1抗體之保護效果
論文名稱(英文) Protection of Anti-Dengue Virus Nonstructural Protein 1 Antibodies in the Wild Type and Humanized Mouse Models
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 102
學期 2
出版年 103
研究生(中文) 李涵
研究生(英文) Han Lee
電子信箱 suemm56@hotmail.com
學號 s46011118
學位類別 碩士
語文別 英文
論文頁數 61頁
口試委員 指導教授-余俊強
共同指導教授-林以行
口試委員-羅伯安德森
口試委員-林秋烽
中文關鍵字 登革病毒  非結構性蛋白1  一致性膜套蛋白區塊三  擬人化小鼠 
英文關鍵字 dengue virus  nonstructural protein 1  consensus envelope protein domain III  humanized mice 
學科別分類
中文摘要 登革病毒 (dengue virus; DENV) 感染可造成登革熱或甚至嚴重致死的登革出血熱或登革休克症狀。迄今仍無許可的疫苗或抗病毒治療。我們先前的研究顯示抗登革病毒非結構性蛋白1抗體會與人類內皮細胞及血小板發生交叉反應,並且導致內皮細胞及血小板的功能失調。我們也發現登革病毒非結構性蛋白1在C 端的部分序列與宿主自身的抗原相似。將抗登革病毒非結構性蛋白1的C 端序列去除後產生之抗體,在細胞或是小鼠活體皆可提供保護性。這個C 端序列去除之非結構性蛋白1 (胺基酸271-352),我們稱為ΔC NS1。此外,由於有效的登革疫苗必須能同時對抗四種血清型的登革病毒,比對四種血清型登革病毒膜套蛋白區塊三的胺基酸序列,我們的合作者開發出一致性膜套蛋白區塊三 (consensus envelope protein domain III; cEDIII)。以cEDIII免疫小鼠,可同時誘發中和性抗體,對抗四種血清型登革病毒。因此,我們將上述兩種蛋白: cEDIII及ΔC NS1融和成一個蛋白,名為cEDIII-ΔC NS1的蛋白質。將cEDIII-ΔC NS1以高分子型奈米複合物做為佐劑免疫小鼠後,此蛋白質並不會對小鼠造成急毒性,也不會延長出血時間。ELISA結果顯示,cEDIII-ΔC NS1引發的抗體量高於ΔC NS1。溶斑減少中和抗體試驗法結果顯示,抗cEDIII-ΔC NS1抗體具有中和登革病毒的能力,且將此抗體被動免疫登革病毒感染之小鼠,可以提供此小鼠治療效果。我們進一步發現單株抗體2E8 並不會辨識登革病毒非結構性蛋白1的C 端部分,並且可以提供小鼠對抗登革病毒感染的保護性。目前為止,仍然沒有一種合適的動物模式可以用來研究登革病毒疾病,由於小鼠並不是登革病毒的天然宿主,所以擬人化小鼠的優勢是對於登革病毒的感病度較高,並且也可以讓我們探討人類細胞對於登革病毒感染的反應。因此,我們建立了兩種擬人化小鼠模式,以人類骨髓的造血幹細胞或人類週邊血單核細胞植入免疫缺陷小鼠。在植入人類骨髓的造血幹細胞之擬人化小鼠模式中,以抗ΔC NS1抗體被動免疫登革病毒感染後的小鼠可以減少被延長的出血時間;在植入人類週邊血單核細胞之擬人化小鼠模式中,我們給予被登革病毒感染的單株抗體2E8後,小鼠局部皮膚出血有減緩的現象。綜合以上結果,cEDIII-ΔC NS1蛋白質及單株抗體2E8可作為治療登革熱的候選標的物,提供了具有潛力的抗登革病毒策略。
英文摘要 Dengue virus (DENV) infection may cause dengue fever or even life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Currently, there are no approved vaccines or antiviral therapies. We previously found that the anti-nonstructural protein 1 (NS1) antibodies (Abs) could cross-react with endothelial cells and platelets and cause their dysfunction due to a molecular mimicry with host self-antigens. The Abs against C-terminus-deleted NS1 provided protective effects both in cell culture and in mice. This NS1 with a deletion at C-terminal amino acids 271-352 was designated ΔC NS1. In addition, the Abs against consensus envelope protein domain III (cEDIII), of which the amino acid sequences are consensus among four serotypes and which was developed by our collaborators, had neutralizing activity against all the four serotypes of DENV. We, therefore, developed a recombinant NS1 by fusing cEDIII and ΔC NS1. We immunized mice with cEDIII-ΔC NS1 proteins encapsulated in the polymer-based nanocomplex as adjuvant. The cEDIII-ΔC NS1 proteins did not cause acute toxicity or prolonged bleeding in mice. An ELISA-based assay showed that the immunization provoked a higher Ab response for cEDIII-ΔC NS1 than ΔC NS1. In addition, anti-cEDIII-ΔC NS1 Abs could neutralize DENV infection in a plaque reduction test. Anti-cEDIII-ΔC NS1 Abs also provided therapeutic effect in DENV-infected wild type (WT) mouse model. We further demonstrated that monoclonal antibody (mAb) 2E8, which did not recognize the C-terminal region of DENV NS1, could provide therapeutic effects in DENV-infected WT mice. So far, there is no ideal animal model for dengue disease studies. Because mice are not natural host for dengue, the advantages of using humanized mice include higher susceptibility to DENV and enhanced opportunity to investigate human cell responses to DENV infection. We have established two models of humanized mice. The NOD/SCID IL2Rγnull mice were reconstituted with human hematopoietic stem cells (HSCs) or human peripheral blood mononuclear cells (PBMCs). Passive immunization with anti-ΔC NS1 Abs could reduce DENV-induced mouse-tail prolonged bleeding time in human HSC-engrafted mice. In human PBMC-engrafted mice, DENV infection induced severe hemorrhage in local skin. Importantly, passive immunization with mAb 2E8 reduced hemorrhage. Taken together, the cEDIII-ΔC NS1 protein and mAb 2E8 are potential candidates to provide protection against DENV infection.
論文目次 Abstract in Chinese I
Abstract III
Acknowledgement V
Table of Contents VI
Table and Figure List X
Abbreviations XI
Introduction 1
Characteristics of dengue virus 1
Epidemiology of dengue virus 3
Clinical symptoms of dengue virus infection 3
The pathogenesis of dengue virus infection 4
Animal models of dengue virus infection 7
Nanoparticles as biocompatible delivery vehicles for protein-based vaccine 7
Humanized mouse model for infectious disease study 8
Specific Aims 10
1 To investigate the safety of immunization of cEDIII-ΔC NS1 protein-encapsulated nanocomplex in wild type mice. 10
2 To examine the neutralization capacity of anti-cEDIII-ΔC antibody by plaque reduction neutralization test. 10
3 To evaluate the therapeutic effect of anti-cEDIII-ΔC NS1 antibody in WT mice. 10
4 To investigate the protective effects of anti-ΔC NS1 antibody in DENV-infected human bone marrow-engrafted humanized mouse model. 10
5 To determine the infection of human peripheral blood mononuclear cells by DENV. 11
6 To investigate the protective effects of monoclonal antibody 2E8 in DENV-infected human peripheral blood mononuclear cells-engrafted humanized mouse model. 11
Materials and Methods 12
1. Materials 12
A-1 Mice 12
A-2 Cell lines 12
A-3 Virus 12
A-4 Preparation of recombinant proteins and Abs 13
A-5 Chemicals and reagents 14
A-6 Antibodies and Kits 16
A-7 Consumables 17
A-8 Instruments 19
2. Methods 20
B-1 Cell and virus cultures 20
B-2 Plaque assay 21
B-3 Plaque reduction neutralizing test 21
B-4 Enzyme-linked immunosorbent assay 22
B-5 Establishment of PBMC-engrafted humanized mice model 22
B-6 Flow cytometry 23
B-7 Immunization model 23
B-8 Therapeutic model 23
B-9 Bleeding time 24
B-10 Immunohistochemistry staining 24
B-11 Statistics 25
Results 26
1 Investigation of the safety of nanocomplex-encapsulated cEDIII-ΔC NS1 protein as an immunogen in wild type mice. 26
1.1 Preparation of recombinant cEDIII-ΔC NS1 proteins. 26
1.2 Immunization with the recombinant cEDIII-ΔC NS1 protein did not show any acute toxicity. 26
2 Examination of the neutralization capacity of anti-cEDIII-ΔC Ab by plaque reduction test. 26
2.1 Neutralization of DENV-2 by anti-cEDIII-ΔC NS1 Ab. 27
3 Evaluation of the therapeutic effect of anti-cEDIII-ΔC NS1 Ab for DENV-2 infection in wild type mice. 27
3.1 Anti-cEDIII-ΔC NS1 Ab reduced DENV-2-induced prolonged bleeding time. 27
4 Investigation of the protective effects of anti-ΔC NS1 Ab in DENV-infected human bone marrow-engrafted humanized mouse model. 28
4.1 Anti-ΔC NS1 Ab reduced DENV-2-induced prolonged bleeding time in humanized mice. 28
4.2 Anti-ΔC NS1 Ab reduced DENV-2-induced NS4B Ag expression in local infection sites of humanized mice. 28
5 Assay for the infection of human peripheral blood mononuclear cells in engrafted mice by DENV. 29
5.1 Mouse engrafted human PBMCs were infectable by DENV-2. 29
6 Investigation of the protective effects of monoclonal antibody 2E8 in DENV-infected human peripheral blood mononuclear cells-engrafted humanized mouse model. 30
6.1 MAb 2E8 may be a potential candidate for antiviral therapy. 30
6.2 MAb 2E8 reduced DENV-induced prolonged bleeding time 8 days post-infection. 30
6.3 MAb 2E8 reduced DENV-2 induced NS4B Ag expression in local infection sites after 8 days post-infection. 30
6.4 MAb 2E8 reduced DENV-2 induced hemorrhage and NS4B Ag expression in local infection sites. 31
Discussion 32
References 39
Table and Figures 47
Appendix 57
Curriculum Vitae 61
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