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系統識別號 U0026-1607201211440600
論文名稱(中文) 探討腸病毒七十一型病毒基因變異與抗原特性 及感染小鼠致死能力的關係
論文名稱(英文) Characterize the effect of genetic variations of enterovirus 71 on antigenicity and mouse lethality
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 2
出版年 101
研究生(中文) 黃聖文
研究生(英文) Sheng-Wen Huang
學號 S58941599
學位類別 博士
語文別 英文
論文頁數 104頁
口試委員 指導教授-王貞仁
召集委員-王憲威
口試委員-余俊強
口試委員-劉校生
口試委員-林貴香
口試委員-施信如
中文關鍵字 腸病毒71型  抗原性  感染力  小鼠致死力 
英文關鍵字 enterovirus 71  antigenicity  infectivity  mouse lethality 
學科別分類
中文摘要 RNA病毒經常呈現基因變異的多樣性,以利於病毒面對不同的環境,及在不同宿主之間散播。近年來,腸病毒七十一型在亞太地區已經成為一個主要造成手足口症伴隨嚴重神經併發症,且造成多次流行的致病原。在此研究中,針對腸病毒七十一型的基因與抗原演化和小鼠致死力特性進行研究。在腸病毒七十一型演化的部分,腸病毒七十一型基因型B5於2008年在台灣引起新一波流行,此波流行為過去十四年來台灣最大的一波流行,分子演化分析指出,在1986到2011年間,主要流行的基因型,由B轉變為C或是由C轉變為B至少三次。另外,利用血清抗體對不同病毒之中和試驗的結果以抗原圖譜分析顯示,造成流行的腸病毒七十一型基因型B5病毒形成另一個不同的群組,並且與基因型B1/B4及C分布在不同的抗原特性區域。此外,全長基因序列分析顯示,在此期間於台灣流行的腸病毒七十一型出現了同一血清型間與不同血清型間的重組,因此建議持續地監控腸病毒七十一型,包括觀察基因演化與抗原變化。在腸病毒七十一型於小鼠適應特性的研究中,我們針對病毒在體外的感染能力決定位點是否會改變在體內對於小鼠的致死力進行探討,我們發現相較於原始病毒株,小鼠適應株會增加病毒的感染力,進而造成對於神經細胞的毒性增加,並使得受感染的新生小鼠致死率增加,我們的結果指出,腸病毒七十一型的外殼蛋白區域是主要影響病毒感染力與小鼠致死力的區域,其中,當病毒株在VP2149的位點由lysine變為 methionine時,或是在VP1145的位點由glutamine變為glutamic acid時,此重組病毒將會產生較高的病毒效價與造成細胞凋亡的能力,而當此兩個位點同時突變時,將會加成遞增機病毒結合到Neuro-2a細胞的能力,並且增加在受感染細胞中RNA的量,同時,兩個位點雙重突變時,將可以明顯地降低新生小鼠受感染之致死劑量,這指出此雙重突變造成病毒對於新生小鼠的致死力增加。總之,VP2149M與VP1145E的突變將會共同地增加腸病毒七十一型結合到細胞與細胞內RNA的累積量,進而影響病毒的體外感染力與小鼠致死力,因此,這兩個突變之結果可以增加腸病毒七十一型的感染力。
英文摘要 RNA viruses likely emergent with high genetic flexibility to facilitate their adaption in contact with limited environment for effective spread between various hosts. In recent years, re-emergent enterovirus 71 (EV71) has been a cause of numerous outbreaks of hand-foot-and-mouth disease with severe neurological complications in the Asia-Pacific region. This study focused on the genetic and antigenic evolution as well as mouse adaption of EV71. In Taiwan, the reemergence of EV71 genotype B5 in 2008 resulted in the largest outbreak of EV71 in the past fourteen years. Phylogenetic analyses revealed dominant genotypic changes from B to C or C to B for at least three times between 1986 and 2008. Furthermore, antigenic cartography of EV71 by using neutralization tests revealed that the reemerging EV71 genotype B5 strains formed a separate cluster distinct from the B1/B4 and C genotypes. Moreover, analyses of full-length genomic sequences of EV71 circulating in Taiwan during this period showed the occurrence of intra- and inter-serotypic recombination. Continuous surveillance of EV71 including the monitoring of genetic evolution and antigenic changes is recommended. In the mouse model, we investigated the effects of infectivity determinants of EV71 on mouse lethality in vivo. We demonstrated mouse-adapted strain increases infectivity, resulting higher cytotoxicity of neuron cells and mortality to neonatal mice than a non-adapted strain. Results pointed to EV71 capsid region determining viral infectivity and mouse lethality. Mutant virus with lysine to methionine substitution at VP2149 (VP2149M) or glutamine to glutamic acid substitution at VP1145 (VP1145E) showed greater viral titers and apoptic effect in Neuro-2a cells. Synergistic effect of VP2149M and VP1145E double mutations enhanced viral binding and RNA accumulation in infected Neuro-2a cells. The dual substitution mutants markedly reduced value of 50% lethal dose in neonatal mice infection, indicating they raised mouse lethality in vivo. VP2149M and VP1145E mutations thus cooperatively promote viral binding and RNA accumulation of EV71, contributing to viral infectivity in vitro and mouse lethality in vivo.
論文目次 Chinese Abstract I
English abstract III
Acknowledgements V
Introduction 1
Enterovirus 71 (EV71) 1
Outbreak of EV71 1
Molecular epidemiology of EV71 3
Genome and structure of EV71 6
Pathogenesis of EV71 7
Specific aims and experimental design 11
1. To evaluate gentic and antigenic evolution of EV71 viruses 13
1.1 To evaluate genetic evolution of EV71 viruses 13
1.2 To evaluate antigenic evolution of EV71 viruses 14
2. To investigate the mouse infectivity of EV71 14
2.1 To investigate viral infectivity and cytotoxicity of EV71 14
2.2 To analyze genetic determinants contributed to mouse adaptation of EV71 15
2.3 To characterize the mechanism of EV71 infectivity 16
Materials and methods 17
Cells and viruses. 17
Sequencing of the EV71 viruses 17
Phylogenetic analyses and estimation of dN/dS ratio in VP1 sequences 18
Recombination analyses 19
Neutralization test and antigenic cartography 19
Construction of infectious cDNA clones. 20
In vitro transcription and RNA transfection. 22
Examination of virus titer and apoptosis. 22
Virus binding assay 22
Examination of RNA accumulation 23
Effect of RNA accumulation in trans 24
In vitro translation/replication of EV71 RNA 24
Flow-cytometric analysis. 25
Examination of virus growth. 26
In vivo mouse model. 26
Statistical analysis. 26
Results 27
Dynamics of Genetic and Antigenic Evolution of EV71 from 1998 to 2008 27
Phylogenetic and epidemiologic analyses of the EV71 VP1 gene 27
Antigenic map of enterovirus 71 28
Evolution analysis of EV71 VP1 29
Intra and inter-typic recombination between EV71 in Taiwan and other HEV-A viruses 30
Characterization of EV71 infectivity and mouse lethality determinants in vitro and in vivo 32
Capsid-coding region of mouse-adapted MP4 strain determined in vitro infectivity 32
Identification of VP2149M and VP1145E contributed to in vitro viral infectivity 34
VP1145E and VP2149M mutations cooperatively enhanced EV71 RNA accumulation in Neuro-2a cells 36
VP2149M and VP1145E cocontributed to in vivo mouse lethality 39
Discussion 42
Conclusions 57
References 58
Appendix 104
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