Please use this identifier to cite or link to this item:
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dc.contributorChi-Chen Linen_US
dc.contributorYu-Hsiang Kuanen_US
dc.contributor.advisorChun-Jung Chenen_US
dc.contributor.authorChou, Ming-Lunen_US
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dc.description.abstractType I interferon (IFN) is the first line of host defense against virus infection. Recent studies indicate the non-structural proteins of Japanese encephalitis virus (JEV) have antagonistic effects on type I IFN in vitro, but it is not consistent with the results in animal experiments and clinical cases. Therefore, we want to clarify whether blocking of type I IFN signaling by JEV is in a cell-specific manner. We found that the RNA expression of type I IFN was increased after JEV infection in microglia, but sightly affected in astrocytes. And its downstream signaling, transducers and activators of transcription (STAT) 1/2 protein family, was obviously phosphorylated in microglia. Astrocytes intrinsically expressed STAT1/2 in activated form, and not altered after JEV infection. Moreover, we also demonstrated similar results in protein expression of ISG15 and viperin, which are IFN-stimulated genes (ISGs). On the other hand, the production of type I IFN in central nervous system (CNS) is little known. Glia cells are numerous in rat cerebral cortex and also important in immunomodulation. Hence, we obversed activation of mitogen-activated protein kinase (MAPK), increased transcription activity of nuclear factor-κB (NF-κB) after JEV infection in mixed glia. It is a pathway involved in the biosynthesis of type I IFN, and regulated by reactive oxygen species (ROS). Further analysis indicated that JEV-induced oxidative press is mainly from superoxide, which is produced through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in microglia. In addition, protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were increased in microglia following JEV infection. Activated microglia, as evidenced by morphological transformation, play roles in neuroinflammation and may indirectly cause neuron death. Molecular pathogenesis of JEV is still unclear, and there is no useful drug to cure Japanese encephalitis patients in clinical. In this study, we pointed out that glia cells produce type I IFN through ROS─MAPK─NF-κB pathway after JEV infection. And activated glia cells not only process inflammatory response, but also indirectly lead to neuron death. Importantly, the sensitivity to type I IFN of microglia and astrocytes seems to be different. Providing a platform for studying molecular pathogenesis of JEV, it is potential to develope another strategy against JEV depend on cell-specific virus susceptibility.en_US
dc.description.abstract第一型干擾素是宿主細胞對抗病毒感染的第一道防線,近來研究指出日本腦炎病毒的非結構蛋白具有拮抗作用,但與活體動物實驗、臨床案例的結果並不一致。因此,我們想要釐清日本腦炎病毒拮抗第一型干擾素是否具有細胞特異性。本篇論文中,以日本腦炎病毒分別感染大鼠大腦皮質初代微神經膠細胞與星狀神經膠細胞,第一型干擾素 RNA 在前者有較為明顯的上升表現,而星狀神經膠細胞處理病毒後,除了本身第一型干擾素 RNA 的表現,僅微幅增加。第一型干擾素下游訊號路徑 signal transducers and activators of transcription (STAT)-1/2 蛋白家族,酪胺酸磷酸化位置在微神經膠細胞中明顯被活化,而星狀神經膠細胞本身就穩定表現活化態 STAT,沒有受到病毒感染而增加蛋白表現的幅度。進而探討下游第一型干擾素誘發基因,ISG15、viperin 抗病毒蛋白產物,也得到類似的結果。 此外,關於中樞神經系統如何產生第一型干擾素,知道的仍舊不多,而神經膠細胞除了參與免疫調節,也佔有大腦皮質大部分比例。因此,我們以日本腦炎病毒感染混合神經膠細胞後,發現 mitogen-activated protein kinase (MAPK) 路徑活化,促使 nuclear factor-κB (NF-κB) 進行轉錄生成第一型干擾素,且受到活性含氧物質的調控。進一步分析,觀察日本腦炎病毒造成的氧化壓力,主要來自微神經膠細胞,經由 nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 產生超氧化物所致。先前實驗室研究已指出神經膠細胞參與發炎反應,間接導致神經元細胞死亡。在此,我們也觀察到病毒感染微神經膠細胞增加 inducible nitric oxide synthase (iNOS)、cyclooxygenase-2 (COX-2) 蛋白表現。 目前針對日本腦炎病患臨床上尚無有效治療方式,相關致病分子機轉的研究有待釐清。在本篇論文中,我們指出 ROS─MAPK─NF-κB 為一條參與神經膠細胞生成第一型干擾素的路徑,且神經膠細胞進行發炎反應間接導致神經元細胞死亡。另外,我們說明不同細胞對於第一型干擾素具有感受性的差異,導致抗病毒能力亦不相同,提供一個思考平台探討日本腦炎病毒致病分子機轉,期許發展出另一種策略對抗日本腦炎病毒。zh_TW
dc.description.tableofcontents目次 誌謝辭------i 中文摘要------ii Abstract------iii 一、緒論------1 1.1. 前言------1 1.2. 日本腦炎病毒簡介------1 1.2.1. 日本腦炎病毒之起源------1 1.2.2. 日本腦炎病毒之分布及流行型態------2 1.2.3. 日本腦炎病毒之傳播途徑------2 1.2.4. 日本腦炎之臨床症狀------3 1.2.5. 日本腦炎之診斷治療------4 1.2.6. 日本腦炎病毒之防疫控管------5 1.2.7. 日本腦炎病毒的病毒分類------5 1.2.8. 日本腦炎病毒的分子結構------5 1.2.9. 日本腦炎病毒在台灣的情況------8 1.3. 中樞神經系統大腦皮質細胞組成簡介------9 1.3.1. 神經元細胞------9 1.3.2. 神經膠細胞------10 微神經膠細胞------10 大神經膠細胞------11 1.4. 第一型干擾素簡介------12 1.4.1. 第一型干擾素的分類------12 1.4.2. 第一型干擾素的產生機制------12 1.4.3. 第一型干擾素下游訊號傳遞路徑之正向活化機轉------13 1.4.4. 抗病毒相關的第一型干擾素誘發基因產物------13 1.4.5. 第一型干擾素下游訊號傳遞路徑之負向抑制機轉------14 1.4.6. 病毒逃脫第一型干擾素免疫作用的機制------14 1.4.7. 第一型干擾素對於中樞神經系統細胞的影響------15 1.5. 研究動機------16 二、材料方法------18 2.1. 抑制劑與試劑------18 2.2. 日本腦炎病毒增殖------18 2.3. 病毒溶斑試驗 (Plaque assay)------19 2.4. 病毒感染細胞------19 2.5. 初代大腦皮質細胞培養 (Rat cerebral cortex primary cell culture)------19 2.5.1. 混合神經膠細胞 (Mixed glia)------20 2.5.2. 微神經膠細胞 (Microglia)------20 2.5.3. 星狀神經膠細胞 (Astrocyte)------21 2.5.4. 神經元/神經膠細胞 (Neuron-Glia)------21 2.5.5. 神經元細胞 (Neuron cell)------22 2.6. 海馬迴組織器官培養 (Hippocampal tissue slice)------22 2.6.1. 利用 PI評估海馬迴離體組織培養之細胞傷害性------23 2.6.2. 海馬迴離體組織培養之螢光染色------24 2.7. 西方墨點法 (Western blot)------25 2.7.1. 蛋白質樣本的製備------25 2.7.2. 細胞膜蛋白質分層萃取------25 2.7.3. 電泳分離蛋白質與轉漬------26 2.7.4. 抗體免疫連結------27 2.8. 反轉錄聚合?鏈式反應 (Reverse transcription, RT-PCR)------27 2.8.1. RNA的抽取、定量------27 2.8.2. RNA的反轉錄------28 2.8.3. cDNA進行聚合?鏈式反應------28 2.8.4. 跑膠分離不同片段長度之核酸產物------29 2.9. 一氧化氮測量------30 2.10. 活性含氧物質測量------30 2.11. DAB免疫細胞染色 (DAB immunocytochemistry)------31 2.12. 免疫螢光細胞染色 (Immunofluorescent staining)------31 2.13. 細胞狀況分析------32 2.13. 1. 細胞毒性分析試驗 (LDH assay)------32 2.13. 2. 細胞活性分析試驗 (MTS assay)------32 2.14. 電泳遷移試驗 (Electrophoretic mobility shift assay, EMSA)------33 2.15. 統計分析------34 三、實驗結果------35 3.1. 日本腦炎感染混合神經膠細胞,導致第一型干擾素的RNA表現,並活化STATs 訊號路徑。------35 3.2. 日本腦炎病毒感染神經元細胞,對神經元細胞造成傷害。------35 3.3. 日本腦炎病毒感染海馬迴離體組織培養,對神經迴區域的細胞造成傷害。------36 3.4. 日本腦炎病毒感染神經膠細胞,會活化 MAPK 訊號路徑並增加 NF-κB 轉錄能力,參與第一型干擾素的生成。------36 3.5. 日本腦炎病毒感染神經膠細胞的過程,抗氧化劑抑制 MAPK- NF-κB 訊號路徑,並調控第一型干擾素的生成。------37 3.6. 日本腦炎病毒感染神經膠細胞,促使微神經膠細胞內活性含氧物質上升。------38 3.7. 日本腦炎病毒感染神經膠細胞,造成微神經膠細胞的 NADPH oxidase 活化。------38 3.8. 日本腦炎病毒感染微神經膠細胞與星狀神經膠細胞,第一型干擾素 RNA 表現量上升幅度在微神經膠細胞較為明顯。------39 3.9. 日本腦炎病毒感染微神經膠細胞與星狀神經膠細胞,STAT1/2 蛋白活化表現在微神經膠細胞較為明顯。------40 3.10. 日本腦炎病毒感染會導致微神經膠細胞內的干擾素誘發基因產物增加。------41 3.11. 日本腦炎病毒感染神經膠細胞,透過氧化壓力影響內源性第一型干擾素所誘發之下游基因產物。------41 3.12. 透過外源性第一型干擾素之給予,可以增加混合神經膠細胞內,病毒引起的干擾素誘發基因之蛋白表現。------42 3.13. 日本腦炎病毒感染神經膠細胞,主要誘發微神經膠細胞參與發炎反應。------42 3.14. 日本腦炎病毒感染活化微神經膠細胞,但並未明顯改變星狀神經膠細胞的型態。------44 3.15. 日本腦炎病毒感染海馬迴離體組織培養,造成神經元細胞損傷、微神經膠細胞增生。------44 3.16. 日本腦炎病毒感染神經元/神經膠細胞,透過神經膠細胞造成神經元細胞相對多的損傷。------45 3.17. 日本腦炎病毒感染混合神經膠細胞,透過 STAT1 路徑增加干擾素誘發基因,並影響一氧化氮合成?、環氧化?的蛋白表現。------46 3.18. 日本腦炎病毒透過 STAT1 的活化,維持微神經膠細胞的存活。------46 3.19. 日本腦炎病毒感染神經膠細胞,會造成微神經膠細胞 STAT3 的活化。------47 四、討論------48 五、圖表------53 六、參考文獻------91 圖表目次 圖3.1 日本腦炎病毒感染混合神經膠細胞,評估第一型干擾素的 RNA 表現之變化。------53 圖3.2 日本腦炎病毒感染混合神經膠細胞,評估誘發 STAT1、STAT2 磷酸化蛋白表現量之變化。------54 圖3.3 日本腦炎病毒感染神經元細胞,評估病毒對於 MAP-2 陽性細胞的傷害程度。------55 圖3.4 日本腦炎病毒感染神經元細胞,測定乳酸脫氫? (LDH) 釋出量的變化。------56 圖3.5 日本腦炎病毒感染海馬迴離體組織培養,評估病毒對於 PI 陽性細胞的影響。------57 圖3.6 日本腦炎病毒感染海馬迴離體組織培養,定量 PI 陽性細胞的表現變化。------58 圖3.7 日本腦炎病毒感染混合神經膠細胞,評估病毒對於 NF-κB 轉錄能力的影響。------59 圖3.8 日本腦炎病毒感染混合神經膠細胞,評估病毒對於 IκB-α、IκB-β 的蛋白質表現量之變化。------60 圖3.9 日本腦炎病毒感染混合神經膠細胞,評估 MAPK 訊號傳遞路徑相關蛋白表現量的變化。------61 圖3.10 日本腦炎病毒感染混合神經膠細胞,評估 ERK、NF-κB 抑制劑對於病毒引起的第一型干擾素RNA表現量之影響。------62 圖3.11 日本腦炎病毒感染混合神經膠細胞之後,評估抗氧化劑對於病毒引起磷酸化 ERK 蛋白表現之影響。------63 圖3.12 日本腦炎病毒感染混合神經膠細胞,評估抗氧化劑對病毒引起 NF-κB 轉錄能力之影響。------64 圖3.13 日本腦炎病毒感染混合神經膠細胞,評估抗氧化劑對於病毒引起的第一型干擾素 RNA 表現量之影響。------65 圖3.14 日本腦炎病毒感染微神經膠細胞 (A) 與星狀神經膠細胞 (B) 3小時後,透過 DCF 偵測細胞內活性含氧物質的變化。------66 圖3.15 日本腦炎病毒感染微神經膠細胞 (A) 與星狀神經膠細胞 (B) 3小時後,透過 DHE 偵測細胞內超氧化物的變化。------67 圖3.16 日本腦炎病毒感染混合神經膠細胞,評估 NADPH oxidase 蛋白單元由細胞質轉位 (Translocation) 至細胞膜的情形。------68 圖3.17 日本腦炎病毒感染微神經膠細胞,評估 NADPH oxidase 蛋白單元轉位至細胞膜的情形。------69 圖3.18 日本腦炎病毒感染星狀神經膠細胞 (A)、微神經膠細胞 (B),評估第一型干擾素的 RNA 表現之變化。------70 圖3.19 日本腦炎病毒感染微神經膠細胞,評估誘發 STAT1、STAT2 磷酸化蛋白表現量之變化。------71 圖3.20 日本腦炎病毒感染星狀神經膠細胞,評估誘發 STAT1、STAT2 磷酸化蛋白表現量之變化。------72 圖3.21 日本腦炎病毒感染微神經膠細胞,評估 STAT1 蛋白轉位至細胞核的情形。------73 圖3.22 日本腦炎病毒感染混合神經膠細胞 (A)、微神經膠細胞 (B)、星狀神經膠細胞 (C) 不同時間點,評估病毒引起 STAT1、STAT2 下游路徑 ISG 相關蛋白表現之變化。------74 圖3.23 日本腦炎病毒感染混合神經膠細胞,評估抗氧化劑對於病毒誘發的STAT 蛋白家族 RNA 表現之變化。------75 圖3.24 日本腦炎病毒感染混合神經膠細胞,評估抗氧化劑對於病毒誘發的STAT1 蛋白家族蛋白表現之變化。------76 圖3.25 日本腦炎病毒感染混合神經膠細胞,評估 IFN-α 對於病毒誘發的訊號路徑之蛋白表現影響。------77 圖3.26 日本腦炎病毒感染不同神經膠細胞,評估不同時間 nitrite 的含量變化。------78 圖3.27 日本腦炎病毒感染海馬迴離體組織培養,評估不同時間 nitrite 的含量變化。------79 圖3.28日本腦炎病毒感染不同神經膠細胞,評估誘發一氧化氮合成? (iNOS) 與環氧化?-2 (COX-2) 蛋白表現量之變化。------80 圖3.29日本腦炎病毒感染微神經膠細胞,評估病毒對於 CD68 陽性細胞的型態影響。------81 圖3.30日本腦炎病毒感染星狀神經膠細胞,評估病毒對於 GFAP 陽性細胞的型態影響。------82 圖3.31日本腦炎病毒感染海馬迴離體組織培養,評估病毒對於 Iba1、MAP-2陽性細胞的影響。------83 圖3.32日本腦炎病毒感染海馬迴離體組織培養,定量 Iba1、MAP-2 陽性細胞螢光強度的變化。------84 圖3.33日本腦炎病毒感染神經元/神經膠細胞,評估病毒對於 MAP-2 陽性細胞的傷害程度。------85 圖3.34日本腦炎病毒感染神經元/神經膠細胞,測定乳酸脫氫? (LDH) 釋出量的變化。------86 圖3.35日本腦炎病毒感染混合神經膠細胞,評估 STAT1 抑制劑對於病毒誘發的訊號路徑之蛋白表現影響。------87 圖3.36日本腦炎病毒感染微神經膠細胞,評估 STAT1 抑制劑對於細胞存活的影響。------88 圖3.37日本腦炎病毒感染混合神經膠細胞 (A)、微神經膠細胞 (B)、星狀神經膠細胞 (C) 不同時間點,評估病毒對於 STAT3 磷酸化蛋白表現量之影響。------89 圖3.38 日本腦炎病毒感染微神經膠細胞,評估 STAT3蛋白轉位至細胞核的情形。------90zh_TW
dc.subjectJapanese encephalitis virusen_US
dc.subjectRat cerebral cortex primary cellen_US
dc.subjectType I interferonen_US
dc.subjectSignal transducer and activator of transcriptionen_US
dc.subjectInterferon stimulated geneen_US
dc.titleRole of Type I Interferons Signaling Pathway during Japanese encephalitis virus Infection in Rat Glial Cellen_US
dc.typeThesis and Dissertationzh_TW
item.fulltextno fulltext-
item.openairetypeThesis and Dissertation-
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