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系統識別號 U0026-2409201209062000
論文名稱(中文) 探討巨噬細胞移動抑制因子及凝血相關自體抗體在登革病毒感染之致病機轉
論文名稱(英文) Study on the pathogenesis of macrophage migration inhibitory factor and coagulation-related autoantibodies during dengue virus infection
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 1
出版年 101
研究生(中文) 莊詠鈞
研究生(英文) Yung-Chun Chuang
學號 s58981125
學位類別 博士
語文別 英文
論文頁數 130頁
口試委員 指導教授-葉才明
召集委員-林以行
口試委員-劉校生
口試委員-林秋烽
口試委員-伍安怡
口試委員-吳漢忠
中文關鍵字 登革病毒  細胞激素  自體抗體 
英文關鍵字 Dengue virus  cytokine  autoantibody 
學科別分類
中文摘要 登革病毒(Dengue Virus, DENV)感染會造成輕微的登革熱(Dengue Fever, DF)和較嚴重之登革出血熱(Dengue Hemorrhagic Fever, DHF)或登革休克症候群(Dengue Shock Syndrome, DSS)。DHF/DSS臨床主要會有血管滲漏(Vascular Leakage)或是出血的症狀發生。對於DENV感染造成DHF/DSS有許多的假說,包括抗體依賴性增強作用及細胞激素的過度活化等;此外,DENV所誘導的自體抗體亦可能參與在致病機轉。在先前的研究中,我們發現登革病患血清中巨噬細胞移動抑制因子(Macrophage migration inhibitory factor, MIF)的表現量與登革病患嚴重程度呈現正相關; 而在MIF基因剔除的小鼠感染DENV後,其病毒複製及血液濃縮的現象比正常小鼠輕微,顯示MIF可能與DENV所造成的血管通透性上升或病毒之複製有關。我們利用MIF重組蛋白或DENV感染的細胞上清液發現MIF能夠促進血管內皮細胞通透性增加,主要是透過上升細胞表面受體CD74及CXCR2/4來影響細胞間緊密連接蛋白ZO-1的分布。動物模式也證實MIF可以促進小鼠腹腔及背部皮下血管通透性的上升。此外,細胞自噬作用(Autophagy)被證實可作用DENV複製的平台,而發炎性細胞激素也被認為可以誘導自噬作用的產生。因此,我們利用重組蛋白來探討MIF在細胞自噬的作用。實驗結果顯示MIF可以透過活性氧化物(Reactive oxygen species, ROS)的產生來誘導細胞自噬;在養分缺乏下誘導的細胞自噬,MIF也會受到ROS的產生而分泌,顯示MIF與ROS之間可以互相調控,進而參與在細胞自噬。此外,MIF、ROS 及細胞自噬在DENV病毒感染時都會上升。當MIF或是ROS被抑制的情況下,細胞自噬以及病毒的複製也會隨之受到抑制。這些結果顯示在DENV感染所誘導的MIF可能參與在血管通透性及DENV複製的調控。
在出血機轉的研究中,先前研究已證實DENV感染會誘導與凝血因子相關的自體抗體。然而,這些抗體對凝血機轉有甚麼影響並不清楚。我們利用DENV免疫小鼠製造單株抗體,並篩選出幾株能夠交叉辨識到纖溶酶原(Plasminogen, Plg)的抗體。其中單株抗體6H11具有絲氨酸蛋白酶(Serine protease)的酵素活性,能夠直接活化Plg或是促進尿素激酶(Urokinase)所誘發的Plg活化。此外,我們發現DENV也能誘導和其他凝血因子如凝血酶(Thrombin)或凝血酶原(Prothrombin)結合的自體抗體。因此,我們從兔子免疫或登革病患的血清中純化出對抗Thrombin的抗體。我們發現這些抗體除了能夠抑制Thrombin的活性之外,也能夠具有類似單株抗體6H11的功能來直接或促進Plg的活化。另一方面,我們也發現單株抗體6H11也能夠辨識到Thrombin並干擾其活性。因此,DENV感染所誘導的抗體可能具有抑制凝血及促進纖溶作用的功能。在疫苗的發展上,可能要避開這些抗體的抗原決定位,以免產生自體抗體而影響凝血作用。
英文摘要 Dengue virus (DENV) infection can cause dengue fever (DF), severed dengue hemorrhage fever (DHF), or dengue shock syndrome (DSS). DHF/DSS patients have symptoms such as vascular leakage and hemorrhage. There are several hypotheses for why DHF/DSS occurs after DENV infection such as antibody-dependent enhancement and cytokines over activation. In addition, DENV-induced autoantibodies might also participate in the pathogenesis of DHF/DSS. In previous study, we found the sera levels of macrophage migration factor (MIF) in dengue patients are correlated with disease severity. In MIF knockout mice, the viral replication and hemoconcentraction are reduced after DENV infection, as compared with wild type mice. This information indicated MIF might play a role in vascular permeability and viral replication. We used MIF recombinant protein and DENV-infected cell supernatant in this study and found MIF could bind to surface receptors CD74 and CXCR2/4 and enhance vascular permeability through disrupt tight junction protein ZO-1 distribution. We also proved injection of MIF into mice could enhance the vascular permeability in vivo. In addition, autophagy has been shown to be involved in DENV replication. Proinflammatory cytokines are also considered to be able to induce autophagy. Therefore, we used recombinant MIF protein to investigate the role of MIF in autophagy. Our data indicated that MIF could induce autophagy of human hepatoma cell line HuH-7 cells though reactive oxygen species (ROS) generation. MIF was also secreted in nutrient depletion-induced autophagy which is ROS dependent. These results indicate MIF and ROS can regulate each other and participate in autophagy. In addition, MIF, ROS, and autophagy are also upregulated during DENV infection of HuH-7 cells. When MIF or ROS was inhibited, autophagy and viral replication were both inhibited. These data suggest MIF induced by DENV infection may participate in regulation of both vascular permeability and DENV replication. Therefore, MIF inhibitor may have both anti-inflammatory and anti-viral effects against DENV infection.
DENV-induced coagulation-related autoantibodies have been suggested to be involved in the mechanism to cause hemorrhage. However, the exact mechanisms of these antibodies to cause coagulation dysfunction are unclear. In this study, we used DENV-immunized mice to generate monoclonal antibodies (mAbs), and screened out several clones which could cross-react to Plasminogen (Plg) and enhanced its activation or enhance urokinase-induced Plg activation. Among them, mAb 6H11 showed the best activity of seine protease. In addition, we found DENV can also induce autoantibodies which could bind to other coagulation factors such as thrombin or prothrombin. Thus, we purified anti-thrombin antibodies from both DENV immunized rabbit sera and dengue patients’ sera. We found these anti-thrombin antibodies not only inhibited thrombin activity, but also shows similar function as mAb 6H11 to enhance Plg activation directly or indirectly. On other hand, we also found mAb 6H11 could also recognize thrombin and interfere its activity. Hence, antibodies-induced by DENV infection may inhibit coagulation or enhance fibrinolysis. In vaccine development, the epitopes recognized by these autoantibodies should be avoided to prevent possible side effect on coagulation.
論文目次 Chinese Abstract….………………………………………………………………...I
English Abstract………………………………………………………………….III
Acknowledgments.……………………………………………………………….V
Table of Contents………………………………………………………………...VII
List of Figures…………………………………………………………………..XIII
List of Abbreviations……………………………………………………...........XVI
1. Introduction…………………………………………………………………….1
1.1 DENV genome and structure…………………………………………...…1
1.1.1 Genome and RNA structure……………………………………….1
1.1.2 Viral structure and protein………………………………………...2
1.2 DENV infection…………………………………………………………..…4
1.2.1 Receptors…………………………………………………………….4
1.2.2 DENV-induced autophagy………………………………………….5
1.2.3 Clinical classification and manifestations…………………………6
1.3 Hypothesis of DHF/DSS……………………………………………………7
1.3.1 Antibody-dependent enhancement……………………...…………7
1.3.2 Complement activation and cytokine-mediated pathogenesis…...8
1.3.3 Immunopathogenesis and autoimmunity………………………….9
1.4 Macrophage migration inhibitory factor (MIF)………………………...10
1.4.1 Function and receptors……………………………………………10
1.4.2 Role of MIF in infectious diseases………………………………...11
1.5 Abnormal coagulation in DENV patients……………………………….12
1.5.1 Coagulation………………………………………………………...12
1.5.2 Abnormal coagulation in DENV patients……..………………....13
1.5.3 Molecular mimicry between DENV and coagulation factors…..13
2. Specific Aims and Experimental Designs……………………………………15
3. Materials and Methods…………………………………………………….…18
3.1 Materials…………………………………………………………………..18
3.1.1 Antibodies and ELISA Kits……………………………………….18
3.1.2 Regents……………………………………………………………..19
3.1.3 Plasmid……………………………………………………………..21
3.1.4 Consumables and devices…………………………………………22
3.2 Methods……………………………………………………………………23
3.2.1 Cells and cell culture………………………………………………23
3.2.2 Preparation of virus stocks, titration and infection……………..23
3.2.3 Gene silencing via short hairpin RNA……………………………24
3.2.4 Recombinant MIF protein………………………………………...25
3.2.5 Western blotting…………………………………………………...25
3.2.6 Function assays of rMIF…………………………………………..26
3.2.7 ELISA……………………………………………………………....26
3.2.8 Inhibitors and treatment………………………………………….27
3.2.9 Immunofluorescent staining………………………………………28
3.2.10 Permeability assays………………………………………………..29
3.2.11 Reverse-transcription PCR (RT-PCR)…………………………...30
3.2.12 LC3-EGFP and ptfLC3 fluorescent assay………………………..30
3.2.13 Nitric oxide (NO), hydrogen peroxide (H2O2), and superoxide detection……………………………………………………………31
3.2.14 Mitochondrial membrane potential (MMP) assay………………32
3.2.15 Patients’ sera……………………………………………………….32
3.2.16 Antibodies generation and epitope mapping…………………….32
3.2.16.1 Generation of polyclonal antibodies…………………….32
3.2.16.2 Generation of monoclonal antibodies…………………...33
3.2.16.3 Epitope mapping using phage-displayed random peptide
……………………………………………………..……33
3.2.17 Plm formation assay…………………………………………….…34
3.2.18 Fibrinogen (Fbg) cleavage analysis……………………………....35
3.2.19 Chromogenic assay of thrombin, Plm, and serine protease activity……………………………………………………………...35
3.2.20 Thrombin time (TT) assay………………………………………...36
3.2.21 Fibrin formation and clot lysis assay……………………………..36
3.2.22 Measurement of Plm and thrombin activity in mice……………37
3.2.23 Statistical analysis………………………………………………....37
4. Results…………………………………………………………………………38
4.1 Pathogenic role of MIF in DENV infection……………………………...38
4.1.1 MIF contributes to vascular permeability increase during DENV infection…………………………………………………………….38
4.1.1.1 DENV infection enhances MIF secretion in HuH-7 cells….38
4.1.1.2 Expression and purification of functional rMIF………..…38
4.1.1.3 DENV-induced MIF enhances vascular permeability of
endothelial cells during infection…………………………...39
4.1.1.4 MIF disarrays ZO-1 distribution in HMEC-1 cells………40
4.1.1.5 MIF enhances vascular permeability in mice……………..41
4.1.2 MIF is involved in autophagy and DENV replication…………...42
4.1.2.1 rMIF induces autophagy in human hepatoma cells………..42
4.1.2.2 rMIF stimulates ROS generation and causes mitochondrial
membrane potential (MMP) loss……………………………43
4.1.2.3 Serum-starvation induces MIF secretion…………………...44
4.1.2.4 Serum starvation-induced ROS generation and autophagy
formation are inhibited by MIF inhibitors, ISO-1…………45
4.1.2.5 MIF depletion reduces serum starvation-induced ROS
generation and MMP loss……………………………………45
4.1.2.6 Depletion of endogenous MIF reduces starvation-induced
Autophagy…………………………………………………….46
4.1.2.7 MIF inhibition reduces DENV-induced ROS generation….46
4.1.2.8 MIF inhibition reduces DENV-induced autophagy and
Replication……………………………………………………47
4.2 Pathogenic role of autoantibodies in DENV infection………………….48
4.2.1 Autoantibodies against Plasminogen (Plg) in DENV infection…48
4.2.1.1 Autoantibodies cross-react to Plg in DENV patients’ and
immunized mice sera………………………………………...48
4.2.1.2 Generation and characterization of Plg cross-reactive
dengue mAb…………………………………………………..48
4.2.1.3 Epitope mapping of Plg cross-reactive monoclonal antibody
6H11…………………………………………………………...49
4.2.1.4 Inhibition of mAb 6H11 and dengue patient’ sera binding to
Plg by phage…………………………………………………..49
4.2.1.5 Plg cross-reactive mAb induce Plg activation and show
serine protease activity………………………………………50
4.2.1.6 Human Plm conversion, Fbg cleavage, and D-dimer
formation induced by Plg cross-reactive mAbs…………….51
4.2.1.7 Plm activity and D-dimer formation induced by 6H11 mAb
in vivo………………………………………………………….52
4.2.2 Autoantibodies against thrombin in DENV infection…………...52
4.2.2.1 DENV infection elicits autoantibodies against human
thrombin and prothrombin………………………………….52
4.2.2.2 DENV immunization elicits autoantibodies cross-react to
several coagulation factors…………………………………..53
4.2.2.3 Characterization of anti-thrombin antibodies (ATA)……..53
4.2.2.4 Both rabbit and human ATA inhibit thrombin activity……54
4.2.2.5 ATA enhance Plg activation and fibrinolysis…………….…54
4.2.2.6 Mab 6H11 shows cross-reactivity to both thrombin and
Plg………………………………………………………..……55
4.2.2.7 Mab 6H11 inhibits thrombin activity and enhance clot
Lysis.…………………………………………………………..55
4.2.2.8 Potential binding sites of mAb 6H11 to thrombin……….....56
4.2.2.9 Rabbit ATA inhibit thrombin activity and enhance
fibrinolysis in mice…………………………………………...56
5. Discussion……………………………………………………………………...58
5.1 Pathogenic role of MIF in DENV infection……………………………...58
5.1.1 MIF-induced by DENV infection enhances permeability……....58
5.1.2 MIF is involved in autophagy and DENV replication…………...62
5.2 Pathogenic role of autoantibodies in DENV infection………………….64
5.2.1 The pathogenic role of autoantibodies against Plg………………64
5.2.2 The pathogenic role of autoantibodies against thrombin...……..67
6. Conclusion……………………………………………………………………..69
7. Reference………………………………………………………………………70
8. Figures and Figure legends…………………………………………………...90
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