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系統識別號 U0026-2206201012582400
論文名稱(中文) 以in vitro 與in vivo 之方式探討腸病毒71型誘發之細胞自噬現象及其在致病性中扮演之角色
論文名稱(英文) Enterovirus 71-induced autophagy detected in vitro and in vivo and its role in pathogenesis
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 98
學期 2
出版年 99
研究生(中文) 王柏舜
研究生(英文) Po-Shun Wang
學號 S4696102
學位類別 碩士
語文別 英文
論文頁數 77頁
口試委員 指導教授-劉校生
口試委員-余俊強
口試委員-洪錦堂
中文關鍵字 腸病毒71型  細胞自噬  細胞自噬流  早期生長反應因子1 
英文關鍵字 Enterovirus 71 (EV71)  Autophagy  Autophagic flux  Early growth response 1 (Egr-1) 
學科別分類
中文摘要 腸病毒71型(EV71)屬於小RNA病毒科,為無套膜包覆之單股正向RNA病毒。迄今EV71感染於臨床上並沒有任何針對EV71之有效抗病毒藥劑及疫苗。細胞自噬為演化下高度保留之蛋白質代謝機轉,細胞內半衰期長之蛋白質及受損胞器,藉形成自噬體之方式將其運至溶酶體分解之。許多研究指出細胞自噬於病毒感染中扮演重要角色。先前我們已證實EV71可感染肌肉細胞株RD與神經細胞株SK-N-SH並誘發細胞自噬,同時亦於受感染EV71之仔鼠頸部脊椎神經元細胞中發現疑似自噬體之囊泡生成。在本篇研究首先證實利用細胞自噬誘導劑tamoxifen可以增強病毒蛋白VP1的表現,然抑制劑3-MA會降低之,顯示EV71誘發細胞自噬之活化有利於病毒複製。再者EV71感染會抑制Erk蛋白磷酸化,然利用表皮生長因子(EGF)處理感染細胞後,證實Erk訊息途徑沒有參與EV71誘發細胞自噬之過程。EV71感染造成自噬蛋白LC3與溶酶體蛋白LAMP1之共位現象(co-localization)。而利用藥劑阻斷自噬體和溶酶體之融合,結果發現LC3表現增強,VP1則受抑制,顯示EV71誘發細胞自噬有助於細胞自噬流(autophagic flux)之進行。我們發現LC3會與核內體(endosome)蛋白MPR共位,顯示EV71會誘導中間囊泡(amphisome)之生合成;LC3會分別與EV71 蛋白2C及3A高度共位,顯示該二蛋白與細胞自噬有互動作用。此外早期生長反應因子1(Egr-1)之表現量在感染細胞中有顯著上升,伴隨LC3表現量增加,顯示EV71感染細胞後可藉活化Egr-1以促進細胞自噬之誘發。有趣地是,在受感染之仔鼠腦內神經細胞發現高量表現之LC3與VP1蛋白,以3-MA處理後之早期,出現病毒量下降,及仔鼠體重上升與臨床症狀減輕之現象,顯示細胞自噬參與EV71之致病過程。總而言之,我們揭示EV71誘發細胞自噬於細胞及動物模式之病程角色,並提供未來可能治療標的之契機。
英文摘要 Enterovirus 71 (EV71) is a non-enveloped positive single-stranded RNA virus, which belongs to the family Picornaviridae. EV71 is an important etiological agent causing sudden death of young children in recent global outbreak. Currently, there is no effective antiviral therapy or vaccines against EV71 infection. Autophagy is an evolutionarily conserved lysosomal process for the degradation and recycling long-lived proteins and damaged organelles in host cells and plays a crucial role in virus infection. We reported that EV71 induces autophagy in muscle RD and neuron SK-N-SH cells. EV71 also induces autophagosome-like vesicles in the cervical spinal neurons of infected suckling mice. (J. Med. Virol. 81:1241-52, 2009). In this study, we demonstrate that EV71 VP1 expression was induced by the autophagy inducer tamoxifen and inhibited by the inhibitor 3-methyladenine (3-MA), indicating that EV71-induced autophagy is beneficial for viral replication. Phosphorylation of extracellular signal-regulated kinase (p-Erk) was suppressed by EV71 infection. However, p-Erk did not participate in EV71-induced autophagic process. EV71 induced co-localization of LC3 and lysosomal-associated membrane protein 1 (LAMP1) protein, and co-localization of LC3 and mannose-6-phosphate receptor (MPR), indicating the amphisome (fusion of endosome and autophagosome) formation. Furthermore, co-localization of LC3 and EV71 2C, LC3 and 3A suggests that EV71 2C and 3A are involved in host autophagic response. Blockage of the fusion of autophagosome and lysosome by NH4Cl and vinblastine caused LC3 accumulation, indicating that EV71 infection triggers the autophagic flux. Transcription factor early growth response 1 (Egr-1) was increased following EV71 infection and associated with LC3 expression, suggesting that Egr-1 may promote autophagy in response to EV71 infection. Intriguingly, in EV71-infected suckling mice, the expression levels of VP1 and LC3 proteins were highly expressed from 12 hr p.i. in the brain neurons. The body weight was increased and disease severity of the mice was attenuated at the early stage after 3-MA treatment. Furthermore, EV71 titer was also suppressed. It suggests that autophagy is involved in EV71-related pathogenesis and promote viral replication. In conclusion, we reveal a potential role of EV71-induced autophagy in viral pathogenesis both in vitro and in vivo.
論文目次 Abstract in Chinese ......................................................................................................I
Abstract........................................................................................................................II
Acknowledgements......................…………………………………………………....IV
Contents.........................................................................................................................V
Abbreviations............................................................................................................VIII
Introduction…………………………………………………………………………..1
Part I. Enterovirus 71 .……………………………………………………...…...…..1
1. The characteristics of enterovirus 71……………………….…………………….1
2. The epidemiology of enterovirus 71……………………………………………..2
3. The clinical symptoms of enterovirus 71 infection………………………………3
Part II. Autophagy……………………………………………………...…………….4
1. The characteristics of autophagy…………………………………………………4
2. The molecular mechanisms of autophagy………………………………………..5
3. The signaling pathway involved in autophagy……………………………….......8
4. Autophagic flux…………………………………………………….…………….9
5. The role of autophagy in viral pathogenesis…………………………...……….10
Part III. Early growth response 1 (Egr-1)…………………………………………14
1. The characteristic of Egr-1………………………………………………...……14
2. The role of Egr-1 in viral pathogenesis……………………………………...….15
3. The molecular mechanisms of Egr-1 regulates autophagy……………..………16
Specific Aims………………………………...………………………………………18
Materials and Methods………………………………………………………..……19
1 Bacteria culture and plasmid preparation……………………………………….19
2 Cell culture, viruses and infection………………………………………………20
3 Plaque assay……………………………………...……………………………..22
4 Immunofluorescence assay…………………………………………………..…22
5 Western blot analysis…………………………………………………………....24
6 Reporter gene assay……………………………………………………..………26
7 Virus inoculation of mice………………………………….……………………26
8 Tissue collection and viral titer measurements……………………...………….27
9 Immunohistochemical staining…………………………………………..……..27
10 Statistic analysis……………………………………………...…………………28
Results…………………………………………….…………………………………29
1 EV71 infection induces autophagic response in infected cells…...…………….29
2 EV71 viral production is affected by the autophagy inducer and the autophagy inhibitor………………………………………..………………………………29
3 The possible signaling pathways participate in EV71-induced autophagy.……30
4 EV71 infection induces autophagic flux in virus-infected cells………………..31
5 EV71 infection induces amphisome formation in virus-infected cells…..……..31
6 EV71 infection induces Egr-1 expression and autophagy in virus-infected cell.32
7 EV71 infection causes severe clinical symptoms in suckling mice....……...…..32
8 EV71 infection induces autophagic response in the brain tissues of the suckling mice……………………………………………………...…………………….33
9 EV71-induced autophagy as well as viral titer are suppressed by the autophagic inhibitor 3-MA………………………………………………………..……….33
Discussion…………………………………………………………………………....35
References……………………………………..…………………………………….41
Figure List
Fig. 1. Autophagy was induced by EV71 infection in RD cells……………..………56
Fig. 2. The effect of autophagy inducer and inhibitor on EV71 production in RD cells……………………………………………………………………………..……57
Fig. 3. The involvement of Erk signaling pathway in EV71-induced autophagy in SK-N-SH cells……………………………………………………………….……….58
Fig. 4. Autophagic flux was induced in RD and SK-N-SH cells by EV71 infection...60
Fig. 5. Amphisome formation was detected in SK-N-SH cells after EV71 infection..63
Fig. 6. Egr-1 promoted autophagy in response to EV71 infection in SK-N-SH cells..65
Figure 7. EV71 mouse-adapted MP4 strain induced clinical symptoms in suckling mice………………………………..…………………………………………………67
Figure 8. Autophagy was induced by EV71 MP4 infection in the brain tissues of the suckling mice………………………………………………………………………....69
Figure 9. Autophagy inhibitor 3-MA suppressed EV71 MP4 viral titer in infected suckling mice……………………………………………………………...………….70
Figure 10. Autophagy inhibitor 3-MA suppressed EV71 MP4-induced autophagy and EV71-related pathogenesis………………………………………………...…………72
Appendix List
Appendix 1. EV71-induced autophagy is beneficial for viral replication and viral protein expression…………………………………………………………………....73
Appendix 2. The process of autophagy………………………………………….......74
Appendix 3. In the ER, poliovirus 2BC and 3A proteins recruit modified LC3 to form a complete autophagosome like vesicle……………………………………….…….75
Appendix 4. The altas of mouse brain anatomy……………………………….…….76
Curriculum Vitae……………………………………………………..…………….77
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