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系統識別號 U0026-2307201612010200
論文名稱(中文) 以次世代基因定序技術發現VP1-31G在腸病毒A71型致死感染中扮演重要角色
論文名稱(英文) Identify VP1-31G in Enterovirus A71 Fatal Infection by Next-Generation Sequencing
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 104
學期 2
出版年 105
研究生(中文) 黃乙惠
研究生(英文) Yi-Hui Huang
學號 T36034026
學位類別 碩士
語文別 英文
論文頁數 58頁
口試委員 指導教授-王貞仁
口試委員-楊孔嘉
口試委員-張權發
口試委員-劉校生
中文關鍵字 A71型  次世代定序  神經毒性 
英文關鍵字 Enterovirus A71  NGS  neuropathogenesis 
學科別分類
中文摘要 腸病毒A71型屬於小RNA病毒家族中的腸病毒屬,為一無套膜的正股RNA病毒。在臨床上,被感染後常引起輕微的手足口症和疱疹性咽峽炎等;有些感染者會引起神經性併發症,如腦炎、急性遲緩麻痺,甚至導致死亡。然而目前對於腸病毒A71型是如何感染中樞神經系統的病毒因子尚未明瞭。本研究利用次世代定序技術分析在1998年一位死亡病患從不同組織分離到的病毒株,以及來自同年其他死亡病例及手足口症病人的病毒株基因。透過次世代定序及基因單倍型分析,我們發現帶有VP1-31G的病毒成為中樞神經組織中的主要的基因單倍型 (haplotype)。此外,在死亡病例中的VP1-31G比例也比手足口症病人高。我們建構了基因重組病毒探討VP1-31這個位點對於腸病毒71型的影響。在腸道細胞中,帶有VP1-31D的病毒比VP1-31G的病毒具有更高的複製速率,然而在神經細胞中帶有VP1-31G的病毒生長速率較快。此外,VP1-31G病毒在競爭中有更好的適應性 (fitness)。進一步利用中性紅試驗,我們發現帶有VP1-31G的病毒在神經細胞中具有較好的脫殼效率。綜合以上實驗結果,我們發現帶有VP1-31G的病毒更有利於在神經細胞中生長,而這可能與腸病毒A71型的神經毒性 (neuropathogenesis)有關。
英文摘要 Enterovirus A71 (EV-A71) is a non-enveloped positive single-stranded RNA virus that belongs to the Enterovirus genus, Picornaviridae family. EV-A71 is a major pathogen causing hand-foot-and-mouth disease (HFMD) or herpangina, but occasionally causes acute flaccid paralysis, encephalitis, and may lead to death. However, it remains unknown how EV-A71 causes neurological disease. In this study, we analyzed the viral genome of isolates from various tissues of a fatal patient, as well as clinical isolates from fatal and HFMD patients from 1998 outbreak in Taiwan by next-generation sequencing (NGS). From the NGS and haplotype analysis, we found that EV-A71 containing VP1-31G became dominant haplotype in central nervous system tissues during infection. In addition, a higher percentage of VP1-31G haplotype of EV-A71 was found from fatal cases than those from HFMD patients. To examine the effect of VP1-31 on viral properties, we constructed recombinant virus using 6359TW98 as backbone by reverse genetics system. The recombinant virus containing VP1-31D had higher replication rate than VP1-31G in DLD-1 cells; however, the virus containing VP1-31G grew faster in SK-N-SH cells. Furthermore, the VP1-31G virus had better fitness in SK-N-SH cells. By the neutral red assay, we found that virus containing VP1-31G possessed viral RNA release advantage in neuronal cells. In conclusion, we found that VP1-31G is advantageous to replication in neuronal cells which may contribute to neuropathogenesis of EV-A71.
論文目次 Chinese Abstract I
Abstract II
Acknowledgement III
Table of contents IV
List of tables VI
List of figures VII
List of appendix figures VIII
Abbreviations IX
Chapter 1 Introduction 1
1.1 Introduction of Enterovirus A71 1
1.1.1 Classification of Enterovirus 1
1.1.2 Structure of Enterovirus A71 1
1.1.3 Clinical manifestation and epidemiology of Enterovirus A71 3
1.1.4 Pathogenesis of Enterovirus A71 4
1.1.5 Transmission route of Enterovirus A71 5
1.1.6 Life cycle of Enterovirus A71 6
1.2 Quasispecies theory 7
1.3 Next-generation sequencing (NGS) 8
1.4 Specific aims 9
Chapter 2 Materials and Methods 11
2.1 Materials 11
2.1.1 Cell line 11
2.1.2 Bacterial 11
2.1.3 Primers 11
2.1.4 Plasmids 12
2.1.5 Enzymes 12
2.1.6 Chemicals and reagents 12
2.1.7 Buffers and solutions 14
2.1.8 Kits 14
2.1.9 Instruments 14
2.2 Methods 15
2.2.1 Cells and virus isolates 15
2.2.2 EV-A71 gene amplify and next generation sequencing 15
2.2.3 Haplotypes analysis 16
2.2.4 Construction of infectious cDNA clones 16
2.2.5 Production of recombinant viruses 17
2.2.6 Immunofluorescence stain (IF stain) 17
2.2.7 Virus growth kinetics 18
2.2.8 Plaque assay 18
2.2.9 Competition assay 18
2.2.10 Virus binding assay 19
2.2.11 Neutral Red infectious center assay (NRIC assay) 19
2.2.12 Thermal stability 20
Chapter 3 Results 21
3.1 Analyze viral genetic variations of clinical isolates from 1998 EV-A71 outbreak 21
3.1.1 Haplotype analysis of isolates from various tissues of a fatal patient 21
3.1.2 VP1-31G proportion analysis of clinical isolates from fatal and HFMD patients ………………………………………………………………………………………………………..22
3.2 Investigation of the effect of VP1-31 on viral properties 22
3.2.1 Production of recombinant virus with VP1-31G variation 22
3.2.2 Comparison of virus replication in vitro 23
3.2.3 Competition between VP-31D and VP1-31G 23
3.2.4 Effect of VP1-31 on virus binding 24
3.2.5 Effect of VP1-31 on virus uncoationg 24
3.2.4 Effect of VP1-31 on virus thermal stability 25
3.3 Adaptive mutation occurred during serial passages 25
Chapter 4 Discussion and Conclusions 27
References 32
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