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系統識別號 U0026-2701201514211301
論文名稱(中文) 登革病毒抗體依賴性增益感染對介白質10生成的調節作用
論文名稱(英文) Regulation of Interleukin-10 Production in Antibody-Dependent Enhancement of 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 103
學期 1
出版年 104
研究生(中文) 蔡宗婷
研究生(英文) Tsung-Ting Tsai
學號 S58981133
學位類別 博士
語文別 英文
論文頁數 81頁
口試委員 共同指導教授-林秋烽
指導教授-林以行
召集委員-劉清泉
口試委員-賴明德
口試委員-張堯
中文關鍵字 登革病毒感染  介白素10  登革病毒抗體依賴性增益感染  肝醣合成酶激酶3  環磷酸腺苷反應元件結合蛋白  脾臟酪氨酸激酶  C型凝集素5A 
英文關鍵字 DENV  IL-10  ADE  GSK-3β  CREB  Syk  CLEC5A 
學科別分類
中文摘要 登革病毒感染被列為全球具有危害性的蚊媒傳染性疾病,可導致登革熱及登革出血熱。可惜目前臨床上缺乏有效的疫苗及抗病毒藥物。臨床研究證實登革重症病患血清中表現抗發炎細胞激素介白素10 (IL-10) 較登革輕症病患高。重要的是內源性登革病毒抗體依賴性增益感染 (ADE) 可導致高量介白素10的生成。然而確切的介白素10生成分子調控機制以及其參與免疫病理機制尚未清楚。本研究計畫即探討登革抗體依賴性增益感染下介白素10的生成調控機制。首先我建立了體外ADE感染模式,結果顯示人類類單核細胞THP-1於抗登革膜蛋白單株抗體存在下感染登革病毒可提高病毒感染率。ADE效應使得介白素10蛋白質表現及其基因轉錄活性增加。我們之前研究的結果得知登革感染可藉由調控蛋白質激酶A/磷脂酰肌醇3激酶/蛋白質激酶B/肝醣合成酶激酶3/環磷酸腺苷反應元件結合蛋白的訊息傳遞誘導介白素10生成。在ADE感染下,可增強登革病毒活化的蛋白質激酶A與磷脂酰肌醇3激酶之活性,也可偵測到登革病毒增強蛋白質激酶B於絲胺酸473位點及肝醣合成酶激酶3於絲胺酸9位點的磷酸化。ADE感染下若施行基因默化於環磷酸腺苷反應元件結合蛋白將顯著降低介白素10之生成。藥物標靶抑制磷脂酰肌醇3激酶、蛋白質激酶A 及脾臟酪氨酸激酶可顯著性降低ADE感染下介白素10的產生。抑制脾臟酪氨酸激酶活性也能降低ADE感染下所引起的蛋白質激酶B 中絲胺酸473位點及肝醣合成酶激酶-3中絲胺酸9位點的磷酸化蛋白質表現。這些結果顯示ADE感染下控制介白素10生成的訊息路徑包括以脾臟酪氨酸激酶調控磷脂酰肌醇3激酶/蛋白質激酶B/肝醣合成酶激酶-3/環磷酸腺苷反應元件結合蛋白的訊息上游路徑。加熱去活性的登革病毒無法誘發介白素10的產生,而紫外線去活性的登革病毒則仍然可以引起介白素10的產生。降低THP-1細胞中C型凝集素5A表現後可顯著性降低登革感染誘導介白素10的產生。此外病毒量而非病毒血清型可以影響介白素10的反應。過去報導指出ADE可促進介白素10/細胞激素信號抑制3蛋白表現並且可能影響干擾素的抗病毒的作用,結果顯示無論在有無ADE的登革感染下,藉由抑制介白素10相關訊號路徑包含環磷酸腺苷反應元件結合蛋白/脾臟酪氨酸激酶/磷脂酰肌醇3激酶/ 蛋白質激酶A及C型凝集素5A,皆可有效阻斷登革病毒量及NS4B表現。這些結果顯示介白素10有利於登革病毒的複製。綜合上述介白素10利於病毒複製。藥物標靶以抑制介白素10可視為潛在的抗病毒治療。
英文摘要 Dengue virus (DENV) infection is a global and aggressive mosquito-borne infectious disease which causes both dengue fever and dengue hemorrhagic fever. Unfortunately, there are no effective vaccines and therapeutic antiviral drugs for clinical use. Accumulated clinical evidence shows that DENV infection induces a high level of anti-inflammatory cytokine interleukin (IL)-10 in patients with severe dengue hemorrhagic fever and dengue shock syndrome as compared with those with mild dengue fever. It is important that the intrinsic antibody-dependent enhancement (ADE) of infection causes higher production of IL-10 which promotes viral replication; however, the underlying molecular mechanisms of IL-10 regulation are still unclear. This study is aimed at investigating the pathogenic role and regulatory mechanism of IL-10 production during ADE of DENV infection. First, I established an in vitro model of ADE infection and discovered that the presence of monoclonal anti-envelope (E) antibody increased the infectivity of DENV in human monocytic THP-1 cells. The effects of ADE were further studied by determining protein expression and transcriptional activation of IL-10. We previously demonstrated that DENV infection induces IL-10 production by deactivating glycogen synthase kinase (GSK)-3β in a sequential protein kinase A (PKA)- and phosphoinositide (PI) 3-kinase/PKB-regulated manner. Under ADE infection, DENV not only caused a significant increase in PI3K and PKA activities, but also induced phosphorylation of PKB at Ser473 and GSK-3β at Ser9. Silencing cAMP response element-binding protein (CREB) decreased IL-10 production. Pharmacological inhibition of spleen tyrosine kinase (Syk), PI3K, and PKA reduced IL-10 production has been confirmed following ADE of DENV infection. Moreover, inhibiting Syk also decreased ADE-induced phosphorylation of PKB at Ser473, GSK-3β at Ser9, and CREB at Ser133, indicating Syk may act upstream of PI3K/PKB/GSK-3β/CREB pathway for ADE-induced IL-10 production. The heat-inactivated DENV was unable to induce IL-10 production in THP-1 cells, whereas ultraviolet-deactivated DENV induced IL-10 production normally. The knockdown of C-type lectin superfamily member 5 (CLEC5A) expression in THP-1 cells showed a significant decrease in IL-10 production after DENV infection. The viral load which is not serotype affected the IL-10 response. Regarding ADE-enhanced IL-10/ suppressor of cytokine signaling 3 (SOCS3) expression may interfere with the antiviral response, results showed that genetically and pharmacologically inhibiting IL-10 signaling (including CREB, Syk, PI3K, PKA, and CLEC5A) significantly retarded DENV replication and NS4B expression no matter whether it is with or without ADE of DENV infection. These results show that IL-10 is beneficial for DENV replication and the target IL-10 may be a potential antiviral treatment.
論文目次 Abstract in English I
Abstract in Chinese III
Acknowledgement V
Content VI
Figure List VII
Appendix List VIII
Abbreviations IX

Chapter 1 Introduction 1
1-1 Epidemiology, clinical classification, and manifestations 1
1-2 Virology- genome, RNA structure, viral structure, and protein 1
1-3 Pathological hypothesis 3
1-3-1 Viral factors 3
1-3-2 Cytokine storm 4
1-3-3 Autoantibody 5
1-3-4 Host genetic factors 5
1-3-5 Antibody-dependent enhancement (ADE) 6
1-4 IL-10 signaling pathway 7
1-5 IL-10 and DENV infection 8
1-6 Glycogn synthase kinase-3 signaling 10
Chapter 2 Objectives and Specific Aims 12
Chapter 3 Materials and Methods 13
3-1 Viruses, cells, and chemicals 13
3-2 Separation of human monocytes 14
3-3 DENV infection 14
3-4 Plaque assay 15
3-5 Western blotting 15
3-6 IL-10 expression 15
3-7 Activity assay 16
3-8 Immunostaining 16
3-9 RNA interference 17
3-10 LDH assay 17
3-11 Statistical analyses 18
Chapter 4 Results 19
4-1 To clarify the different of IL-10 signal pathway between DENV and ADE infection 19
4-1-1 DENV infection induces IL-10 production and activation in monocytes 19
4-1-2 ADE of DENV infection amplifies IL-10 production through Syk-regulated PI3K/PKB/GSK-3β/CREB signaling 19
4-2 To study the synergistic effects of FcγR and other receptors on IL-10 signaling pathway 20
4-2-1 Heat-inactivated DENV does not cause IL-10 production in monocytes 20
4-2-2 CLEC5A/Syk signaling regulates DENV-induced IL-10 production 21
4-2-3 The relationship between the expression of CLEC5A, viral protein, and IL-10 in monocyte 21
4-2-4 Viral load, but not serotype, affects DENV-induced IL-10 production 22
4-3 To identify the biological function of IL-10 in DENV and ADE infection 22
4-3-1 DENV-induced IL-10 production facilitates virus replication. 22
Chapter 5 Conclusion 24
Chapter 6 Discussion 25
6-1 The pathogenic roles of IL-10 compared with this study and others in DENV infection 25
6-2 IL-10 signaling as the strategy for DENV to escape immune surveillance 25
6-3 The potential receptors and signaling pathways for DENV-induced IL-10 27
6-4 The effect of IL-10 production for DENV infection 28
6-5 The importance of GSK-3 inactivation in microbial infection 29
6-6 The role of IL-10 for DENV therapy 30
Chapter 7 References 32
Figures 56
Figure 1. Electron micrographs of DENV-infected THP-1 cells 56
Figure 2. DENV infection induces IL-10 production and activation in monocytes 57
Figure 3. ADE infection enhances viral replication 59
Figure 4. ADE infection increases IL-10 production 60
Figure 5. ADE of DENV infection amplifies IL-10 production through Syk-regulated PI3K/PKB/GSK-3b/CREB signaling 61
Figure 6. Syk signaling regulates DENV-induced IL-10 production 62
Figure 7. Supernatants of C3/36 cells and heat-inactivated DENV do not cause IL-10 production in monocytes 63
Figure 8. DENV induces IL-10 production in TIM-1- or Axl-independent manner 64
Figure 9. CLEC5A receptor regulates DENV-induced IL-10 production 65
Figure 10. The relationship between the expression of CLEC5A, viral protein, and IL-10 in monocytes 66
Figure 11. Viral load, but not serotype, affects DENV-induced IL-10 production 67
Figure 12. Regulation of IL-10 affects DENV replication in THP-1 cells 68
Figure 13. Regulation of IL-10 affects DENV replication in human monocytes 69
Figure 14. Treatment of inhibitors of Syk, PI3K, and PKA does not cause cytotoxicity in DENV-infected monocytes under ADE 70
Figure 15. Dual hypothetical models for IL-10 regulation in ADE of DENV-infected monocytes 71
Appendix 72
Appendix I. Appendix I. Schematic representation of DENV genome and life cycle 72
Appendix II. The pathogenesis hypothesis of DHF/DSS 73
Appendix III. The transcription factors regulation of IL-10 in different cells 74
Appendix IV. IL-10 signaling pathway 75
Appendix V. The regulation of IL-10 expression by viral infection 76
Appendix VI. The serum/plasma levels of IL-10 in dengue patient 77
Appendix VII. The signaling pathway of CREB 78
Appendix VIII. The relationship among ADE, IL-10 and disease pathogenesis in
DENV infection 79
Curriculum Vitae 80


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