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系統識別號 U0026-1402201201455500
論文名稱(中文) 腸病毒71型基因5端非轉譯區功能與毒性之研究
論文名稱(英文) Characterization of 5′-Untranslated Region of Enterovirus 71 on Viral Translation and Virulence
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 100
學期 1
出版年 101
研究生(中文) 葉明德
研究生(英文) Ming-Te Yeh
學號 s5893138
學位類別 博士
語文別 英文
論文頁數 148頁
口試委員 指導教授-王貞仁
口試委員-劉校生
口試委員-陳舜華
口試委員-余俊強
口試委員-胡小婷
口試委員-林貴香
口試委員-張堯副
召集委員-王憲威
中文關鍵字 腸病毒71型  毒性  內核醣體進入區  5端非轉譯區 
英文關鍵字 EV71  virulence  IRES 
學科別分類
中文摘要 腸病毒71型(EV71)是具有神經侵犯能力的再現性新興病毒,在世界各地尤其亞太地區造成多次大流行,但其毒性因子與致病機制仍有待研究。為了增加對腸病毒71型病毒毒性與致病機制的了解,我們計畫研究病毒5端非轉譯區二級結構在病毒複製中的角色,並利用小鼠感染模式尋找腸病毒71型的毒性決定位置。
腸病毒71型與其他腸病毒一樣,5端非轉譯區被認為具有對病毒轉譯和複製相當重要的RNA二級結構。為了確認這些二級結構對病毒轉譯與複製的重要性,我們首先建立了由5端非轉譯區、螢光基因、2A-3D非結構蛋白及3端非轉譯區構成的複製子系統(replicon)及帶有腸病毒71型病毒基因全長的感染性克隆(infectious clone),並且確認當RNA轉染到細胞中之後可以進行轉譯與複製,並藉由系列刪除複製子與感染性克隆5端非轉譯區遠端與近端的序列再將其RNA轉染到SK-N-SH細胞中以評估5端非轉譯區二級結構對病毒轉譯與複製的影響。我們發現刪除遠端似苜蓿葉結構(Cloverleaf)雖然對其在兔子網狀紅血球細胞萃取液(rabbit reticulocyte lysate)的細胞外轉譯幾乎沒有影響,但其複製子與感染性克隆在SK-N-SH細胞中會失去轉譯與複製的能力。而刪除5端非轉譯區近端序列的結果顯示完整的內核醣體進入區(IRES)對於病毒轉譯是必要的,而其下游的片段(第581到745核苷酸)的存在可以進一步增加病毒轉譯的能力。
利用臨床分離株尋找腸病毒71型毒性決定基因的部分,我們研究了病毒株237在小鼠感染模式中病毒毒性強於病毒株4643的毒性決定基因。基因比對分析顯示這兩株病毒之間有非常多的基因變異位置,藉由建立一系列帶有237與4643病毒株5端非轉譯區片段置換的感染性克隆,並以重組病毒以腹腔注射感染小鼠驗證病毒毒性,我們發現一段位在SL II上半部、由12個核苷酸組成的片段能顯著的影響感染小鼠平均存活天數、存活率與疾病嚴重程度。帶有來自237病毒株這12個核苷酸片段的複製子RNA在轉染到小鼠L929細胞中也呈現較高的轉譯活性與複製速率,將感染性克隆RNA轉染到L929細胞後以西方點墨法偵測病毒轉譯產物也進一步確認來自237病毒株這12個核苷酸的片段可以加強病毒轉譯活性;而hnRNP A1可能是造成轉譯活性不同的宿主蛋白之一。此外,我們導入一系列的點突變到這個片段之中,結果發現5端非轉譯區的第158個位置由237病毒株的胞嘧啶(Cytosine)改變為4643株的尿嘧啶(Uridine)時,病毒轉譯能力會顯著降低,並且會使感染小鼠的平均存活天數與存活率增加,這些結果顯示腸病毒71型5端非轉譯區的C158不但是一個新的病毒轉譯活性決定位置,也是新發現的重要病毒毒性決定位置。
英文摘要 Enterovirus 71 (EV71) has reemerged as a neuroinvasive virus responsible for several large outbreaks in the Asia-Pacific region but virulence determinants and pathogenesis remain to be explored. This study aims to characterize the roles of 5′-UTR in virus replication and to identify molecular determinant for viral virulence in a mouse infection model.
The 5′-untranslated region (UTR) of EV71 contains RNA secondary structures which may affect viral translation and replication as other enteroviruses. To define roles of these RNA secondary structures, EV71 subgenomic replicons composed of 5¢-UTR, firefly luciferase gene, 2A-3D nonstructural region and 3¢-UTR; and full-length infectious clones were established. In addition, EV71 replicons and infectious cDNA clones with 5′-UTR series deletion from distal- or proximal-end were constructed and transfected into SK-N-SH cells to examine their effect on translation and replication. Deletion of cloverleaf (CL) at distal-end had little effect on in vitro translation using rabbit reticulocyte lysate, but abolished translation and virus replication in SK-N-SH cells, indicating critical role of CL with host factors modulating viral translation and replication. Serial deletions at 5′-UTR proximal end on replicon suggest that intact IRES is required for viral translation while sequence from nucleotide 581-745 may further optimize the translation.
To identify virulence determinant of naturally circulating virus, we investigated increased virulence of EV71 clinical isolated 237 as compared with isolate 4643 in a mouse infection model. Sequence analysis revealed numerous genetic variations between the two isolates. A fragment 12 nucleotides in length in stem loop (SL) II of 237 5′-UTR visibly reduced survival time and rate in mice was identified by constructing a series of infectious clones harboring chimeric 5′-UTR. In cells transfected with bicistronic plasmids and replicon RNAs, the 12-nt fragment of isolate 237 enhanced translational activities and accelerated replication of subgenomic EV71. The effect on viral translation was further confirmed by Western blot analysis of viral translated products in infectious RNA transfected L929 cells. A host protein hnRNP A1 was shown to account for the differential translation activity mediated by EV71 5¢-UTR. In addition, tissue viral load analysis suggested that the 12-nt fragment affected neurovirulence and fitness to replicate in CNS in mice. Finally, change from cytosine to uridine at nucleotide 158 of 5′-UTR was proven to determine viral translation and EV71 virulence in mice. Results collectively indicated C158 as major virulence determinant of EV71 in mice.
Our study provides direct evidences that RNA secondary structures in EV71 5′-UTR contribute to viral translation and replication. Also, this study reveals a pivotal role of novel virulence determinant C158 on virus translation in vitro and EV71 virulence in vivo.
論文目次 Table of Contents
Abstract i
Abstract in Chinese iii
Acknowledgements iv
Table of Contents vi
List of Tables x
List of Figures xi
List of Supplementary Tables xii
List of Supplementary Figures xiii
List of Appendices xiv
List of abbreviations xv
1. Introduction 1
1.1. Virology 1
1.2. Life cycle and replication 2
1.3. Clinical diseases and epidemiology 4
1.4. Pathogenesis 6
1.5. Host factors contribute to viral life cycle 6
1.6. Virulence determinant 8
Specific aims 10
2. Materials and methods 12
2.1. Materials 12
2.1.1. Cell lines 12
2.1.2. Viruses 12
2.1.3. Bacteria 12
2.1.4. Animals 13
2.1.5. Reagents 13
2.1.6. Enzymes 15
2.1.7. Oligos 15
2.1.8. Plasmids 18
2.1.9. Kits 19
2.1.10. Antibodies 19
2.1.11. Buffers and Solutions 20
2.1.12. Consumables 21
2.1.13. Equipments 22
2.2. Methods 23
2.2.1. Cell culture 23
2.2.2. Virus culture 23
2.2.3. Preparation of competent cells 23
2.2.4. DNA transformation 24
2.2.5. Colony PCR 24
2.2.6. Nucleic acid purification 24
2.2.6.1. RNA extraction (Total, viral) 24
2.2.6.2. PCR purification and gel extraction 24
2.2.6.3. Plasmid mini preparation 25
2.2.6.4. Plasmid midi preparation 25
2.2.7. Construction of subgenomic EV71 replicons 26
2.2.8. Synthesis of replicon RNA in vitro 26
2.2.9. Translation of RNAs in rabbit reticulocyte lysates 27
2.2.10. Replicon RNA transfection 27
2.2.11. Luciferase activity assay 28
2.2.12. Construction of EV71 infectious clones 28
2.2.13. Generation of recombinant viruses from infectious clones 28
2.2.14. Plaque assay 29
2.2.15. Immunofluorescent stain of EV71 30
2.2.16. Viral growth kinetic assay 30
2.2.17. Temperature sensitivity assay 30
2.2.18. Mouse survival assay 30
2.2.19. Sequencing and sequence analysis 31
2.2.20. RNA secondary structure prediction 31
2.2.21. Construction of bicistronic reporter plasmids 31
2.2.22. Plasmid DNA transfection 32
2.2.23. Reporter activity assay 32
2.2.24. Cloning and expression of hnRNP A1 32
2.2.25. Western blot analysis 33
2.2.26. Statistical analysis 33
3. Results 34
3.1. Construction and characterization of subgenomic EV71 replicons 34
3.2. Intact IRES domain was required while SL VI/VII and linker region may optimize EV71 translation 34
3.3. CL domain contributed to EV71 translation and replication 35
3.4. EV71 isolate 237 was more virulent than isolate 4643 in mice 36
3.5. Isolates 4643 and 237 showed distinct biological properties 36
3.6. Numerous genetic variations between isolates 4643 and 237 37
3.7. Viral 5′-UTR correlated with distinct virulence of the two unadapted EV71 isolates 37
3.8. Mapping of virulence determinant in EV71 5′-UTR 38
3.9. Upper stem of SL II in EV71 5′-UTR affected viral translation and replication 40
3.10. Upper domain of SL II affected EV71 replication in mice 41
3.11. Single nucleotide determined EV71 virulence in mice 41
4. Discussions 43
4.1. Functional analysis on RNA secondary structures in EV71 5′-UTR 43
4.1.1. SL VI/VII and linker region may optimize EV71 translation in SK-N-SH cells 43
4.1.2. CL domain was required for EV71 translation in SK-N-SH cells 44
4.1.3. Partial 5′-UTR deleted virus may be applied in vaccine development 44
4.2. Single nucleotide C158U substitution was sufficient to determine EV71 virulence in mice 44
4.2.1. SL II determined virulence of various enteroviruses 45
4.2.2. Effects of reduced translation on virulence 46
4.2.3. SL II upper stem determined neurovirulence of EV71 47
4.2.4. Host factors responsible for the differential virulence of EV71 remains to be identified 47
4.2.5. Significance of nt. 158 in EV71 clinical isolates 48
4.2.6. Proposed solutions to the contrary EV71 virulence between human and mice 49
5. Conclusions 50
6. References 51
7. Tables 63
8. Figures 66
9. Supplementary chapter 98
9.1. Natural selection from host shapes genome composition of EV71 99
9.2. Avirulent and virulent EV71 show distinct codon usage bias 100
9.3. Evaluation of the degree of codon usage bias of avirulent and virulent EV71 101
9.4. Codon usage bias which affects translation efficiency may play a role to virulence of positive sense RNA viruses 102
9.5. References for supplementary chapter 102
9.6. Supplementary Tables 105
9.7. Supplementary Figures 110
10. Appendices 118
11. Publication 137
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