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研究生:張家銘
研究生(外文):Chia-MingChang
論文名稱:金銀花茶及微小RNA let-7a 抑制腸病毒71型之複製
論文名稱(外文):Honeysuckle and microRNA let-7a inhibit EV71 replication
指導教授:劉校生
指導教授(外文):Hsiao-Sheng Liu
學位類別:碩士
校院名稱:國立成功大學
系所名稱:微生物及免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:英文
論文頁數:61
中文關鍵詞:腸病毒71型微小核醣核酸let-7a金銀花茶
外文關鍵詞:Enterovirus 71 (EV71)microRNA (miRNA)let-7aHoneysuckle
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腸病毒71型屬於RNA 病毒中的小RNA病毒科,感染之後會造成嚴重的中樞神經疾病,目前在臨床上仍無可有效預防或治療疫苗或藥物。微小RNA是一種小片段,不會轉譯出蛋白質的核醣核酸,藉由降解目標訊息核糖核酸或抑制蛋白質合成來扮演基因調控的角色,目前已有許多的研究證實MicroRNAs的表現跟病毒的感染有關,這些MicroRNAs 分別扮演促進或抑制病毒複製之角色,來源也可能是宿主或病毒本身所製造。南京大學甘黛蒂老師的研究中發現,使用金銀花茶餵食九週大C57BL/6小鼠之後,有132個微小RNA在小鼠血液裡面高度表現,經由軟體的分析預測let-7a有可能結合腸病毒71型的基因上的結構蛋白VP2以及5端未轉譯區。在本篇實驗中,我們首先驗證了在七天大的小鼠實驗中金銀花茶可讓血液中let-7a高度表現,也證實金銀花茶的萃取物可讓細胞中的let-7a 高度表達。本研究亦證實攜帶腸病毒71型VP2 及 5’UTR基因的報導質體,let-7a可以抑制冷光酵素基因之活性,證實let-7a的抑制現象是藉由直接結合目標基因所造成。在感染腸病毒71型的RD肌肉細胞與SK-N-SH神經細胞中高度表達let-7a實驗中,let-7a可以抑制病毒VP2蛋白質以及核酸的合成以及負股核酸的複製,也對於病毒的效價有明顯抑制的效果,在病毒感染七天大ICR仔鼠一天之後使用顱內注射let-7a(2或4 M)的動物實驗中也證實了let-7a可抑制病毒VP2蛋白質與核酸的表現,同時在病毒效價與疾病嚴重程度上也有抑制的現象。此外,在七天大仔鼠感染腸病毒71型後,每天餵食金銀花茶兩次,四天之後,小鼠的疾病病徵與小鼠腦中病毒的VP2蛋白質表現量以及效價都有明顯的降低,表示金銀花茶也可有效抑制腸病毒71型的感染。

綜合以上的實驗結果,在本篇研究中發現微小RNA 在細胞與小鼠中皆可有效抑制病毒的感染,其作用包括抑制病毒VP2蛋白質及核酸的表現以及降低病毒的效價及疾病病徵。也證實金銀花茶可在細胞以及小鼠中誘導let-7a高度表現,在腸病毒71型感染小鼠之後餵食金銀花茶同時也有抑制病毒的作用。金銀花茶除了透過調控let-7a來抑制病毒感染之外是否還有其他未知的機制抑制腸病毒71型的效果仍是未來值得探討的問題。金銀花茶及let-7a或許可成為在研究抑制腸病毒71型藥物或健康食品上一個新的目標。此外,本篇研究也提供了透過飲食來調控內源性微小RNA來達到抑制病毒的概念。

Enterovirus 71(EV71) , a single positive strand RNA virus of Picornaviridae, causes severe neurological symptoms, such as encephalitis and poliomyelitis-like paralysis. MicroRNA(miRNA) is a small, non-coding endogenous RNA, functions as a transcription regulator by suppressing the expression of the target genes through degrading the mRNA or inhibiting translation. MiRNAs play a crucial role in host defense of viral infection. Honeysuckle is a traditional Chinese medicine with anti-bacteria and antiviral activity. The miRNA expression profile of mice after honeysuckle treatment has been established and one of the most significantly up-regulated microRNAs let-7a showing anti-EV71 potential after software prediction. There are two target sequences on EV71 strain 4643. One is the region 236-253 of 5’UTR and the other is 1234-1256 of EV71 VP2 region. In this study, we initially demonstrated that honeysuckle induced let-7a expression by in vitro and in vivo studies and furthermore demonstrated the inhibitory effect of let-7a on EV71 infectious clones pMP4-y-5 and pTOPO-4643. Let-7a overexpressed in human rhabdomyosarcoma (RD) and neuroblastoma (SK-N-SH) cells inhibited virus VP2 protein, RNA synthesis and descreased viral titer. Let-7a inhibition of EV71 infection was also demonstrated in sucking mice. Furthermore, in sucking mice, honeysuckle attenuated virus pathogenesis and inhibited viral VP2 protein synthesis. In contrast, VP2 RNA synthesis was not suppressed, it suggests that honeysuckle may inhibit virus infection by a microRNA-independent pathway. Honeysuckle and let-7a may be the new candidates for anti-EV71 development. This study also provides a direction toward prevention of virus infection by ingesting healthy foods to induce endogenous microRNA expression.
Contents
Abstract in Chinese I
Abstract IV
Ackowlegement VI
Abbreviations X
Introduction 1
Part I: Enterovirus 71 1
1. The characterics 71s of Enterovirus 1
2. The clinical symptoms of enterovirus 71 infection 2
3. The anti-EV71 vaccine and drug development 2
Part II: microRNA 4
1. The biogenesis of microRNA 4
2. Virus infection, immunity and miRNAs 5
3. microRNA let-7 family 7
Part III: Honeysuckle 8
1. The property of honeysuckle 8
2. The antiviral activity of honeysuckle 9
Specific aims 10
Materials and methods 11
A. Bacteria culture and plasmid preparation 11
B. Cell culture, virus and infection 12
C. Plaque assay 13
D. Immunofluorescence assay 14
E. Western blot analysis 15
F. RNA extraction, RT-PCR and real-time PCR 16
G. Reporter gene assay 17
H . Virus inoculation of mice 18
I. Tissue collection and viral titer measurement 18
J. Immunoprecipitation of miR-Ago2 complex 19
Results 21
Honeysuckle induces let-7a expression both in vitro and in vivo 21
MicroRNA let-7a binds with VP2 and 5’UTR target sequences of EV71 genome 21
Overexpressed let-7a inhibits EV71 infection in cells 22
let-7a inhibits EV71 infection in suckling mice 23
let-7a interacts with EV71 genome 24
Honeysuckle inhibits EV71 infection in suckling mice 24
Discussion 26
Reference 29
Figures list
Figure. 1 Honeysuckle treatment induces let-7a expression both in vitro and in vivo 38
Figure 2. The Let-7a suppressed the expression of 4643 and MP4 strain infectious EV71 clones in BT7-H cells. 40
Figure 3. Demonstration of let-7a specifically targets to VP2 and 5’UTR gene sequence. 41
Figure.4 The optimal expression level and time of the ectopic let-7a expression level in RD and SK-N-SH cells.. 42
Figure. 5 Overexpressed let-7a in infected RD cells inhibits EV71/4643 replication.. 45
Figure. 6 Overexpressd let-7a in infected SK-N-SH cells inhibits EV71 replication. 47
Figure.7 let-7a treatment inhibits EV71/MP4 pathogenesis in ICR suckling mice 51
Figure. 8 let-7a physically interacts with EV71 genome in Ago2 complex. 53
Figure. 9 Honeysuckle treatment attenuates EV71/MP4 pathogenesis in ICR suckling mice. 56
Figure 10 Virus infection inhibits endogenous let-7a expression 57
Appendix list
Appendix 1. The flow chart of let-7a and honeysuckle treatment in ICR suckling mice 58
Appendix 2. The interaction between microRNA and virus infection 59
Appendix 3. The biogenesis of microRNAs 60
Curriculum Vitae…………………………………………………………...61


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