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系統識別號 U0026-2209201600435000
論文名稱(中文) 探討登革病毒感染誘發TNF-α生成的分子機制
論文名稱(英文) Investigating the Molecular Mechanism of TNF-α Production in 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 105
學期 1
出版年 105
研究生(中文) 鄭怡琳
研究生(英文) Yi-Lin Cheng
學號 S58021080
學位類別 博士
語文別 英文
論文頁數 119頁
口試委員 指導教授-林以行
指導教授-林秋烽
召集委員-張志鵬
口試委員-劉清泉
口試委員-張堯
口試委員-余佳益
中文關鍵字 登革病毒  腫瘤壞死因子-α  誘導性一氧化氮合酶  一氧化氮  NF-κB  TLR3  NS2B3  Nrf2  C型類凝集素5A  內質網壓力 
英文關鍵字 DENV  TNF-α  iNOS  NO  NF-κB  TLR3  NS2B3  Nrf2  CLEC5A  ER stress 
學科別分類
中文摘要 由於登革病毒感染的高流行率及缺乏有效的治療方式,使得登革熱仍威脅著全球人類的健康。雖然造成嚴重登革病症的病理機制尚未完全釐清,促發炎細胞激素—腫瘤壞死因子-α (tumor necrosis factor-α; TNF-α) 的增加可能參與在嚴重病症的發展中。至今,造成此發炎反應活化的分子機制仍未釐清。本論文將探討在登革病毒感染下TNF-α產生的分子機制。結果將可應用在登革疾病中的分子致病機轉並作為治療標靶。儘管一般認為轉錄因子NF-κB的活化可參與在促發炎的反應,例如TNF-α的表現以及一氧化氮的產生,但在登革病毒感染下活化這些發炎反應的分子機制目前仍未被清楚的研究。因此在論文的第一部分將研究NF-κB在登革病毒感染下所產生之TNF-α及誘導性一氧化氮合酶/一氧化氮 (inducible nitric oxide synthase/nitric oxdie; iNOS/NO) 的角色。我們目前的結果指出在登革病毒感染的小鼠巨噬細胞RAW264.7中,TNF-α及iNOS皆會有轉錄及轉譯後修飾所調控的增加,並伴隨NO的產生。當我們利用藥物抑制NF-κB的活化,iNOS/NO的生合成及TNF-α的產生即被抑制。透過抑制氧化壓力的產生,我們也排除了在登革病毒感染下NF-κB在氧化壓力訊息調控中的可能角色。藥物抑制TLR3可部分抑制NF-κB的活化,然而只有效的阻止了iNOS/NO的生合成,卻無法抑制長時間 (>24小時) TNF-α的產生。相較於TLR3,病毒蛋白NS2B3則可以獨立地誘導NF-κB活化而調控TNF-α的產生。綜合以上研究,我們證明了登革病毒感染誘導不同的NF-κB活化路徑,分別調控iNOS/NO及TNF-α的表現。研究證實在登革病毒感染下重要的TNF-α調控因子是訊息傳遞受器C型類凝集素5A (C-type lectin domain family 5, member A; CLEC5A)。根據一高通量的研究發現CLEC5A是nuclear factor (erythroid-derived 2)-like 2 (Nrf2)的目標基因之一。在論文的第二部分將探討登革病毒感染下活化的Nrf2對CLEC5A誘導的TNF-α產生之分子調控機制及新穎角色。結果顯示登革病毒感染選擇性地活化了Nrf2。隨著內質網壓力的產生,protein kinase R-like ER kinase (PERK) 促進了Nrf2所調控CLEC5A轉錄機制的活化而增加了CLEC5A的表現。在登革病毒感染後,Nrf2-CLEC5A 交互作用的下游訊息增強了非TLR3調控的TNF-α產生。強制表達病毒蛋白NS2B3會誘導Nrf2入核及活化並使CLEC5A表現而增加了登革病毒誘導的TNF-α產生。動物模式研究則在登革病毒感染的鼠腦中驗證了Nrf2誘導 CLEC5A 及 TNF-α的表現。以上結果證明登革病毒感染透過增加CLEC5A 的量而造成Nrf2調控的TNF-α產生。綜而言之,這些結果提供了在登革病毒感染下TNF-α產生的詳細分子機制,而參與在這些路徑中的分子也許可作為登革疾病治療的可能目標。
英文摘要 Infection of dengue virus (DENV) threatens global public health due to its high prevalence and the lack of effective treatments. Although the pathogenesis of severe dengue is still largely unknown, an increase in a pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), is reported to be involved in development of severe disorders. However, the molecular mechanisms underlying this inflammatory activation remain undefined. This thesis is aimed at examining the underlying mechanisms of TNF-α production in DENV infection. Results obtained may have implications on molecular pathogenesis and therapeutic targets in dengue diseases. Although the activation of the transcription factor NF-κB is generally involved in pro-inflammatory responses, such as TNF-α expression and also nitric oxide (NO) generation, it has never been clarified in DENV infection. Hence, in the first part of thesis, the role of NF-κB in TNF-α production and inducible nitric oxide synthase/nitric oxide (iNOS/NO) biosynthesis during DENV infection were investigated. Results showed that in addition to TNF-α production in DENV-infected murine macrophage RAW264.7 cells, iNOS was transcriptionally and post-translationally elevated and accompanied by NO generation. Pharmacologically inhibiting NF-κB activation abolished iNOS/NO biosynthesis and TNF-α production. With inhibition, the potential role of NF-κB in oxidative signaling regulation was prevented during DENV infection. Pharmacological inhibition of TLR3 partly decreased NF-κB activation; however, it effectively abolished inducible iNOS/NO biosynthesis but did not inhibit long-termed (>24 hour) TNF-α production. In contrast to TLR3, viral protein NS2B3 also independently contributed to NF-κB activation to regulate TNF-α production. These results show the distinct pathways for NF-κB activation caused by DENV infection individually for the regulation of iNOS/NO and TNF-α expression. The other critical regulator of TNF-α in DENV infection is the signaling receptor C-type lectin domain family 5, member A (CLEC5A). Based on a high-throughput study, CLEC5A is one of target genes of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In the second part of thesis, the molecular regulation and the novel role of activated Nrf2 for CLEC5A-regulated TNF-α expression in DENV infection were clarified. Results showed that DENV infection selectively activated Nrf2. Following endoplasmic reticular (ER) stress, protein kinase R-like ER kinase (PERK) facilitated Nrf2-mediated transcriptional activation of CLEC5A to increase CLEC5A expression. Signaling downstream of the Nrf2-CLEC5A interaction enhances Toll-like receptor 3 (TLR3)-independent TNF-α production following DENV infection. Forced expression of the NS2B3 viral protein induced Nrf2 nuclear translocation/activation and CLEC5A expression which increases DENV-induced TNF-α production. Animal studies confirmed Nrf2-induced CLEC5A and TNF-α in brains of DENV-infected mice. These results demonstrate that DENV infection caused Nrf2-regulated TNF-α production by increasing levels of CLEC5A. Taken together, these data provide the detailed mechanism of TNF-α production during DENV infection. The molecules involved in these pathways may be potential targets for anti-DENV diseases.
論文目次 Abstract in English I
Abstract in Chinese III
Acknowledgement V
Contents VII
Figure lists X
Abbreviations XII
Chapter 1 Introduction 1
1-1 Dengue virus (DENV) 1
1-1-1 Epidemiology of DENV 1
1-1-2 Dengue disease manifestation and classification 1
1-1-3 Structure and proteins of DENV 2
1-1-4 Life cycle of DENV 4
1-1-5 Pathogenesis of dengue hemorrhagic fever/dengue shock syndrome 5
1-1-5-1 Viral factors 5
1-1-5-2 Autoimmunity 6
1-1-5-3 Antibody-dependent enhancement 6
1-1-5-4 Cytokine storm 6
1-1-5-5 Host factors 7
1-2 The pathogenic role of TNF-α in DENV-induced hemorrhagic disorders 7
1-3 Role of transcription factors in DENV infection 8
1-4 Nuclear factor-κB (NF-κB) 8
1-4-1 Role of NF-κB in DENV infection 9
1-5 C-type lectin domain family 5, member A (CLEC5A) 11
1-5-1 Role of CLEC5A in DENV infection 11
1-6 Nuclear respiratory factor-2 (Nrf2) 12
1-6-1 Activation of Nrf2 12
1-6-2 Activation of Nrf2 by ER stress 13
1-6-3 Implication of Nrf2 on viral infection 13
Chapter 2 Objectives and Specific Aims 15
Chapter 3 Materials and Methods 18
3-1 Antibodies (Abs) and reagents 18
3-2 Cell culture and virus culture 18
3-3 DENV infection 19
3-4 Plaque assay 20
3-5 Plasmid overexpression 20
3-6 Immunostaining 20
3-7 Western blotting 21
3-8 Detection of NO production 22
3-9 Intracellular ROS assay 22
3-10 CignalTM finder pathway reporter assay 22
3-11 Antioxidant response element (ARE) reporter assay 23
3-12 Luciferase reporter assay 23
3-13 Reverse-transcription (RT)-PCR and quantitative (q)PCR 24
3-14 ChIP assay 25
3-15 TNF-α, IL-6, and IP-10 expression 25
3-16 RNA interference (RNAi) 26
3-17 Animals 26
3-18 IHC staining 27
3-19 Transmission electron microscopic (TEM) analysis 28
3-20 Statistical analysis. 28
Chapter 4 Results 29
4-1 DENV infection transcriptionally and translationally upregulates iNOS/NO biosynthesis and TNF-α production. 29
4-2 DENV infection causes NF-κB activation. 29
4-3 DENV infection induces the expression of TNF-α, iNOS and NO in an NF-κB-regulated manner. 30
4-4 DENV-induced ROS independent NF-κB activation, TNF-α production, and iNOS/NO biosynthesis. 30
4-5 Heat-inactivated DENV induces NF-κB activation, TNF-α production and iNOS/NO biosynthesis inefficiently. 31
4-6 TLR3 contributes to NF-κB activation of iNOS/NO biosynthesis but not TNF-α production. 31
4-7 DENV protease NS2B3 also promotes NF-κB activation to induce TNF-α production. 32
4-8 DENV infection induces Nrf2 activation in mononuclear phagocytic cells. 33
4-9 DENV induces Nrf2 activation through ER stress-PERK signaling. 34
4-10 Nrf2 determines CLEC5A expression by targeting the Clec5a gene during DENV infection. 35
4-11 Signaling of Nrf2-CLEC5A contributes to TNF-α production during DENV infection. 36
4-12 DENV NS2B3 is involved in ER stress induction, Nrf2 activation, CLEC5A upregulation, and TNF-α production. 37
4-13 ATRA treatment suppresses CLEC5A expression and TNF-α production in a suckling mice model. 38
Chapter 5 Discussion 40
5-1 The role of ROS in the generation of nitrite 40
5-2 The diverse effects of molecular regulation on NF-κB 40
5-3 The roles and mechanisms of NF-κB activation during DENV infection 41
5-4 The function of TNF-α and iNOS/NO in DENV pathogenesis 42
5-5 Mechanisms of TNF-α production during DENV infection 42
5-6 Mechanisms of TNF-α-induced hemorrhage during DENV infection 44
5-7 Regulation of CLEC5A 44
5-8 Role of NS2B3 in DENV infection 45
5-9 Role of Nrf2 in virus infection 46
5-10 Effect and mechanism of ATRA on Nrf2 activation and viral replication 46
5-11 Host factors involved in DNEV infection 47
5-12 Distinct roles of host TLR3 and viral NS2B3 during DENV infection 48
Chapter 6 Conclusion 49
References 51
Figures and Figure legends 68
Appendix 95
Curriculum vitae 100
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