臺灣博碩士論文加值系統

登革熱是一個再度興起的傳染病，遍布在超過100多個國家，包含非洲、東南亞、美洲以及西太平洋等等都可發現它的傳染。因為全球暖化的現象，登革病毒感染的威脅正在增加中。登革病毒感染後會引起發燒、出血甚至伴隨休克症候群的出血症狀。細胞自噬是一種細胞中代謝的機制，用以分解受損的胞器以及錯誤堆疊的蛋白，這個機制被指出會協助登革病毒的複製。最近一篇文獻顯示辛德畢斯病毒會和細胞自噬中的攜帶蛋白p62作用而導致被細胞自噬所清除。但在我們的實驗卻顯示p62似乎會協助登革病毒複製。相較於登革感染的野生型小鼠纖維母細胞，在p62蛋白缺陷時，感染登革病毒後所偵測到的病毒蛋白、釋出的病毒顆粒及病毒RNA都較少。而在穩定表現登革基因細胞中，p62蛋白的表現量降低也會顯著地抑制登革病毒蛋白的產生。這個p62蛋白協助登革病毒複製的角色不只侷限小鼠纖維母細胞中，也同樣可以在肝細胞及單核球細胞中發現。而在野生型或p62蛋白缺陷細胞中，病毒與受器結合、細胞內噬、干擾素活化、啟動細胞自噬的程度並沒有差異。另外，因p62蛋白缺陷所導致的油滴堆積也不是抑制登革病毒複製的原因。但當p62蛋白缺陷細胞被登革病毒感染後，NF-κB會高度磷酸化及入核，而在p62蛋白缺陷細胞中若藉由抑制劑BAY 11-7082來抑制NF-κB活化後，則可以恢復登革病毒在p62蛋白缺陷細胞中的複製。此外，我們也發現p62蛋白缺陷細胞在被登革病毒感染後，活化的NF-κB會引發高量IL-6分泌。而從共軛焦顯微鏡中發現p62蛋白會與登革病毒的prM、E、NS2A及NS3蛋白共位的結果，暗示p62蛋白可能會與這些病毒蛋白作用而協助病毒複製。我們發現了p62蛋白在登革病毒複製上的新角色，也提供了一個未來在登革病毒感染下以p62來當作標靶來治療的可能。

Dengue is a re-emerging disease which is endemic in more than 100 countries throughout Africa, South-East Asia, America, and the Western Pacific. Due to global warming effects, the dengue virus (DV) threat is broadening in the world. The symptoms are febrile illness called dengue fever to dengue hemorrhagic fever and dengue shock syndrome. Autophagy, a cellular catabolic system responsible for damaged organelles and misfolded proteins degradation, is reported to facilitate DV replication. A recent study showed that sindbis virus is associated with an autophagy adaptor protein p62 that leads to elimination of virus by autophagy. However, our data here indicate that p62 seems to be required for DV replication. Compared to WT MEF cells, less virus proteins, released DV particles and DV RNA were detected in DV-infected p62-deficient MEF cells. Significant decreased DV protein translation was also observed in p62 knockdown DV-replicon stable expressing cells. This facilitating role of p62 to DV replication is not limited in MEF cells but also in hepatocyes and monocytes. There were no differences in virus cell binding, endocytosis, interferon activation and autophagy induction between DV-infected WT and p62-deficient cells. Lipid accumulation by p62 deficiency also showed no contribution to DV replication. However, DV triggered high NF-κB phosphorylation and nuclear translocation in p62-deficient cells. The reduced DV replication can be rescued by inactivation of NF-κB with inhibitor BAY 11-7082 in p62-deficient cells. Moreover, we found that NF-κB responsible cytokine IL-6 was highly produced in DV-infected p62-deficient cells. The co-localization of p62 with DV prM, E, NS2A and NS3 proteins from confocal microscopy observation indicates that p62 might interact with DV proteins to facilitate virus replication. Our findings uncover a new role of p62 in facilitating DV replication and also provide a potential therapeutic target for dengue infection.

中文摘要 I
Abstract III
致謝 V
總目錄 VII
圖目錄 X
縮寫索引 XI
緒論 1
研究動機與實驗設計 11
材料與方法 12
A.材料
1. 實驗動物 12
2. 細胞株與培養 12
3. 菌種與質體 12
4. 細菌培養液 13
5. 抗體 13
6. 試劑 17
7. 塑膠、玻璃製品 23
8. 儀器 24
9. 登革病毒株 25
B.方法
1. 從小鼠腹水純化抗體 25
2. 登革病毒的培養 26
3. 登革病毒力價 (titer)濃度的測定 26
4. 以流式細胞儀分析結合到細胞表面的登革病毒 27
5. 以流式細胞儀分析細胞的增強性綠螢光蛋白 (EGFP) 27
6. 以流式細胞儀偵測細胞內病毒蛋白含量 27
7. 西方墨點法 28
8. 偵測登革病毒NS1 mRNA的表現 28
9. 免疫螢光染色 (IFA, Immuno fluorescence assay) 29
10. 細胞轉染(Transfection) 30
11. 酵素免疫分析法(ELISA) 30
12. 以shRNA抑制蛋白表現 30
13. 蛋白冷光儀測量 31
14. 統計分析 31
結果 32
一、p62蛋白可以促進登革病毒的複製 32
二、p62協助登革病毒的複製現象並不只在單一細胞株中發生，而是一種普遍的現象 33
三、p62不參與登革病毒與細胞的結合及後續的病毒內噬作用 34
四、p62蛋白缺陷沒有誘導第一型干擾素 (IFN-β, interferon) 增加而抑制登革病毒的複製 35
五、p62蛋白缺陷沒有影響登革病毒所誘發的細胞自噬作用 36
六、p62蛋白缺陷所導致的油滴累積不會影響登革病毒的複製 36
七、在登革病毒感染下，p62蛋白缺陷的小鼠纖維母細胞中所引起的NF-κB較為活化 37
八、阻斷NF-κB的路徑可以提高登革病毒在p62蛋白缺陷的小鼠纖維母細胞中的感染率 37
九、登革病毒透過NF-κB活化來促使p62蛋白缺陷的細胞產生高量的IL-6 38
十、p62蛋白可以直接和登革病毒雙股RNA與病毒蛋白結合 38
討論 40
結論 50
參考文獻 51
圖.. 63
作者簡歷 83

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