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研究生： 高宜聲
Kao, Yi-Sheng
論文名稱： 登革病毒透過integrin-linked kinase誘發suppressor of cytokine signaling 3 的表現進而抑制第一型干擾素訊息傳導
Dengue virus inhibits type I interferon signaling via integrin-linked kinase-mediated suppressor of cytokine signaling 3 induction
指導教授： 張志鵬
Chang, Chih-Peng
學位類別： 碩士
Master
系所名稱： 醫學院 - 微生物及免疫學研究所
Department of Microbiology & Immunology
論文出版年： 2015
畢業學年度： 103
語文別： 英文
論文頁數： 68
中文關鍵詞： 登革病毒 、整合素連接激酶 、第一型干擾素 、細胞素信號傳導抑制因子3
外文關鍵詞： Dengue virus, Integrin-linked kinase, Type-I interferon, Suppressor of cytokine signaling 3
相關次數： 點閱：83  下載：1 
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    • 登革病毒的感染是全球重要的公衛問題。病毒感染後的症狀包括:輕症的登革熱及嚴重的登革出血熱或是登革休克症候群。然而，目前對抗登革病毒的藥物甚至是疫苗都仍處於臨床試驗階段。先天免疫反應，特別是第一型干擾素（IFN-α/β），是宿主防禦病毒感染的第一道防線。然而已有多篇文獻指出，登革病毒會與許多不同的宿主因子相互作用來逃脫干擾素誘導之免疫反應。不過詳細的機制，尚未完全釐清。整合素連接激酶(integrin-linked kinase, ILK）是一種廣泛表達於細胞中的絲氨酸/蘇氨酸蛋白激酶，具有連接細胞外分子訊息到細胞內信號通路的能力。透過激活整合素連接激酶能夠調節多種細胞功能，包括腫瘤的形成或是調控克沙奇病毒B3型 (Coxsackievirus B3) 的複製。然而，整合素連接激酶與登革病毒間的關係尚未有相關報導。根據我們的實驗數據顯示，在缺乏整合素連接激酶表現的細胞中，其登革病毒產量顯著降低。這顯示整合素連接激酶是登革病毒複製時的重要宿主因子。另外，我們也發現整合素連接激酶並不影響細胞表面與病毒結合的能力，但依然影響登革基因質體 (DENV-replicon) 的表現，表示整合素連接激酶是調控病毒與細胞結合後的複製步驟。另外，實驗結果呈現整合素連接激酶並不會增加登革病毒所誘導產生的第一型干擾素，卻會負向調控第一型干擾素下游的信息傳遞訊號以及抗病毒基因的表達。而且此現象發生的機制是在登革熱病毒感染之下，刺激整合素連接激酶並活化Akt/ERK/NF-κB 這條路徑，誘發產生抑制細胞因子信號3（SOCS3）進而抑制干擾素的訊息傳遞來幫助病毒的複製。根據以上實驗結果，我們推測整合素連接激酶透過負向調控第一型干擾素的信息傳遞訊號，以增進登革病毒複製能力以及疾病的發展。因此，我們的研究揭露的整合素連接激酶過去從未發現的新功能，而整合素連接激酶在未來可作為一個具潛力的抗病毒藥物研發之目標。

    Dengue virus (DENV) infection causes a wide range of disease ranging from dengue fever to potentially fatal dengue hemorrhagic fever or dengue shock syndrome. Currently there are no approved vaccines or antiviral drugs against dengue infection. Innate immune responses, particularly type-I interferon (IFN-α/β), are the first lines of defense against viral infections. Unfortunately, DENV interacts with host factors to escape from IFN responses, and the detailed mechanisms are not totally understood. Integrin-linked kinase (ILK) is a widely expressed serine/threonine protein kinase which connects extracellular molecules to intracellular signaling pathways. By activating ILK, a number of cellular functions can be modulated, including tumorigenesis or Coxsackievirus B3 replication. However, the role of ILK in DENV infection remains uncertain. Here, we showed that dengue viral titers are reduced in ILK inhibited cells. Moreover, inhibition of ILK suppresses DENV replicon expression, but no difference is seen in DENV binding in both control and ILK-silenced cells. This indicates that ILK is required for DENV replication after virus entry. Hence, we further investigated whether ILK regulates DENV replication through the IFN pathway. Our results revealed that there is no difference in induction of IFNα/β between DENV-infected control and ILK-silenced cells. Nevertheless, the downstream responses of IFNs, such as STAT1/2 activation or interferon-stimulated genes (ISG) expression, were upregulated in DENV-infected ILK-silenced cells. In contrast, the suppressor of cytokine signaling 3 (SOCS3), which is able to block IFNs signaling is suppressed. This ILK-mediated SOCS3 induction was found to antagonize DENV infection-triggered IFN signaling and ISG expression. Furthermore, we clarified that ILK may activate the Akt/ERK/NF-κB pathway to induce SOCS3 expression that is required for DENV replication. In conclusion, we uncovered a new regulatory role of ILK in IFN signaling, and targeting ILK may be a potential antiviral therapeutic for future drug development.

    中文摘要 I Abstract II Acknowledgements III Table of contents V Abbreviations IX I. Introduction 1 I.1 Virology of dengue virus 1 1.2 Pathogenesis of dengue virus 3 1.3 Host factors 4 1.4 The battle between innate immune response and DENV 5 1.5 Suppressor of cytokine signaling 3 (SOCS3) regulates the JAK-STAT signaling 6 1.6 Integrin-linked kinase signaling transduction cascades 7 1.7 ILK and infection disease 8 II. Objective and Specific Aims 10 III. Materials and methods 11 A. Materials 11 A-2. Cell lines 11 A-3. Virus 12 A-4. Bacteria and plasmids 12 A-5. Antibody 13 A-6. Reagents 15 B. Methods 21 B-1. Virus culture 21 B-2. UV-inactivated DENV 21 B-3. Plaque assay 21 B-4. DENV infection 22 B-5. Western blotting 22 B-6. Flow cytometry 22 B-7. RT-PCR and Q-PCR 23 B-8. IFA, Immunofluorescence assay 24 B-9. Transfection 25 B-10. Lentiviral-based RNAi gene knockdown 25 B-11. Luciferase reporter assay 25 B-12. ELISA 26 B-13. Lactate dehydrogenase (LDH) releasing assay 26 B-14. Intracerebral injection mouse model 26 B-15. Statistical analyses 27 IV. Results 28 IV-1. ILK regulates DENV replication 28 IV-2. ILK regulates DENV replication after virus entry 29 IV-3.ILK inhibition has no effects on DENV-induced apoptosis and autophagy 30 IV-4. Knockdown of ILK does not increase production of IFN-α/β/λ 30 IV-5. Knockdown of ILK enhances downstream responses of IFNs 31 IV-6. Dengue virus infection triggers ILK-dependent SOCS3 induction 32 IV-7. Inactivated dengue virus is unable to induce SOCS3 32 IV-8. SOCS3 inhibition enhances IFN signaling to suppress DENV replication 33 IV-9. ILK-induced SOCS3 expression is dependent on Akt/ERK/NF-κB activation 34 V. Conclusion 36 VI. Discussion 37 VII. References 41 VIII. Figures 48 Figure 1. DENV infection activates ILK in A549 cells. 48 Figure 2. ILK inhibition reduces DENV viral protein expression. 49 Figure 3. Replication of DENV RNA is reduced in ILK knockdown cells. 50 Figure 4. ILK ablation reduces replication of all four serotypes of DENV. 51 Figure 5. Inhibition of ILK has no effect on DENV binding, but reduces DENV-replicon expression. 52 Figure 6. Knockdown of ILK does not enhance DENV-induced apoptosis. 53 Figure 7. Knockdown of ILK does not affect DENV-induced autophagy. 54 Figure 8. Knockdown of ILK does not increase production of IFN-α/β/λ. 55 Figure 9. ILK inhibition enhances STAT1/2 phosphorylation and ISG expression. 56 Figure 10. Dengue virus infection triggers ILK-dependent SOCS3 induction. 57 Figure 11. Inactivated dengue virus is unable to induce SOCS3 expression. 58 Figure 12. SOCS3 inhibition enhances IFN signaling to suppress DENV replication. 59 Figure 13. ILK-mediated SOCS3 expression attenuates IFN-induced STAT1 and STAT2 activation. 60 Figure 14. ILK-mediated SOCS3 expression is dependent on NF-κB activation 61 Figure 15. ILK-mediated SOCS3 expression is dependent on ERK/ NF-κB activation. 62 Figure 16. Dengue virus infection triggers ILK-associated Akt/ERK/NF-κB activation and SOCS3 induction. 63 Figure 17. Proposed model of dengue virus-triggered inhibition of type I interferon signaling via ILK-mediated SOCS3 induction. 64 IX. Appendix 65 Appendix 1. Genome map of DENV replicon. 65 Appendix 2. ILK kinase domain has the dominant role to induce SOCS3 expression during DENV infection. 66 Appendix 3. ILK inhibitor was able to decrease SOCS3 induction and reduce DENV replication in vivo. 67 Appendix 4. ILK inhibition decrease EV71 VP-1 expression. 68

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