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研究生:吳正男
研究生(外文):Cheng Nan Wu
論文名稱:腸病毒71型之病毒特性與感染機制研究及應用
論文名稱(外文):Molecular Study of the infectious mechanism of Enterovirus 71 and its application
指導教授:何美鄉何美鄉引用關係
指導教授(外文):Mei Shang Ho
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:171
中文關鍵詞:腸病毒71型動物模式感染性 cDNA疫苗DNA疫苗
外文關鍵詞:Enterovirus 71animal modelinfectious clonevaccineDNA vaccine
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腸病毒71型疫情爆發於台灣1998年夏季,造成將近100名的嬰幼兒死於此次的疫情中,然真正的致病機轉卻所知不多,且此病毒的流行陸續於2000、2001年在台灣出現。分析近年來世界各地腸病毒71型的流行情況,可以歸納出其主要的症狀皆不大相同,包括1997年馬來西亞所造成的手足口症,無菌性腦膜炎,心肌炎。1987年美國費城所造成的類小兒麻痺症候群,1983到1987年中國大陸所造成的手足口症,1975年保加利亞流行所造成的類小兒麻痺症候群等。而1998年台灣的流行,經病理分析之結果,應為肺出血休克症侯群。歸納近年來腸病毒71型爆發流行與各地散發性類小兒麻痺症候群的報告,腸病毒71型已被學界認為是小兒麻痺病毒根除以後,最重要的小兒神經毒性病毒。分析腸病毒71型的序列指出,這些分離株彼此間核酸差異不大。為了瞭解此病毒的毒理機轉與所引起的病理反應,以感染新生幼鼠之動物模式為研究基礎,病毒71型造成受感染幼鼠橫紋肌出現嚴重肌纖維凝固樣壞死現象,並感染腰椎部前角之運動神經元之類神經細胞等,最後造成幼鼠死亡。為了穩定腸病毒71型RNA基因體,利用反轉錄方法建構具感染性的病毒cDNA (infectious clone),用以分析病毒感染機制和神經毒性決定基因之所在。結果顯示infectious clone經轉殖至細胞後,能夠產生新的且具感染力的病毒顆粒。因VP1蛋白質在細胞受體與病毒結合上極為重要,故以SOPMA方式預測VP1之二級結構在多種picornavirus中,而歸納出其N 端具有Helix-Turn與保留性proline的結構,此motif普遍存在所有腸病毒VP1蛋白質的N端。利用infectious clone做點突變,將VP1之N端二個proline突變為lysine後病毒失去感染力,進一步實驗證實其影響在病毒RNA脫蛋白鞘decoating的步驟上。
對於腸病毒71型疫情的控制上,疫苗的發展仍為最上策。故利用現有的疫苗免疫方法—去活化病毒、重組蛋白質疫苗、或發展中之DNA 疫苗,此三種不同型態的抗原,用以評估腸病毒71型疫苗的最佳抗原選擇。此三種免疫方式,皆可以產生相似程度的中和性抗體,但去活化病毒可以產生較高的總IgG體與較高的T細胞增生反應,分析細胞激素的結果顯示去活化病毒處理的組別,主要以IL-4、IL-10為主;DNA疫苗處理過的的組別,主要以IFN-含量最高,而重組VP1蛋白質這組則在IL-10有較高的含量。這三種不同性質抗原免疫方式皆可保護幼鼠抵抗病毒致死劑量之挑戰,但仍以去活化病毒所得到的保護效果最好。
Enterovirus 71 (EV71), the newest member of Enteroviruses (Picornavirudae), has caused several large outbreaks including severe neurological diseases in children in recent years. Various viral isolates, including a tissue culture-adapted laboratory strain, have demonstrated different phenotypes such as growth rate in tissue culture and varying degrees of virulence in newborn mice. Genetic analysis of these viruses revealed differences in only a small percentage of nucleotides in both coding and noncoding regions. Mice infection models were attempted unsuccessfully in adult inbred, outbred or immune-deficiency mice. However, in newborn mice of all strains tested, a laboratory-adapted strain, termed YN3, inoculate resulted in hind limb paralysis and eventual death within two weeks post viral challenge. In order to dissect the viral proteins that are essential to these observed viral phenomena, we constructed plasmids encoding the complete cDNA of these EV71 genomes. The RNA transcripts of the full length cDNA EV71 genome, derived from in vitro transcription, are fully infectious when transfected into Vero cells, i.e., virus particles may be recovered from the culture medium of the transfected Vero cells. Mutant and Chimera EV71 clones were than generated from these constructs to study targeted virus proteins and altered biological properties. One motif located on the N-terminus of VP1, which was identified by analyzing VP1 genes of 12 Enteroviruses using SOPMA method to predict secondary protein structures. This motif contains helix, coil structure and proline residues upstream, which we prove to be essential to the virus infectivity by using the infectious cDNA system and it mutants. When the two prolines were replaced by leucines, no infectious virus particle could be recovered. However, when this leucine mutant was blindly passaged 5 times, a few plaques appeared. Sequencing analysis of these plaques showed reverse mutations of the leucine back to proline. Our data suggest that proline motif is essential for virus infectivity.
Since no effective antiviral agents are available, developing vaccines for primary prevention is considered to be the best choice among control strategies against EV71. We compared the inactivated virus vaccine with subunit vaccines - VP1 DNA vaccine or recombinant VP1 protein, in its ability to elicit maternal antibody and to provide protection against lethal infection of EV71 in suckling mice. Prior to gestation, all three groups of vaccinated dams possessed similar levels of neutralizing antibody. With a high challenge dose, suckling mice born to dams immunized with inactivated virus showed 80% survival. The subunit vaccines provided protection only at a lower challenge dosage, with 40% survival for DNA vaccine and 80% survival for VP1 protein. The cytokine profile produced by splenocytes showed a high level of IL-4 in the inactivated virus group, high levels of IFN- and IL-12 in the DNA vaccine group, and high levels of IL-10 and IFN-in the VP1 protein group. Overall, the inactivated virus elicited a much greater magnitude of immune response than the subunit vaccines, including total IgG, all 4 IgG subtypes, and T helper cell responses; these antibodies were shown to be protective against lethal infection when passively transferred to susceptible newborn mice. Our data indicated that inactivated virus is the choice of vaccine preparation capable of fulfilling the demand for effective control, and that VP1 subunit vaccines remain promising vaccine strategies that require further refinement.
目 錄 1
英文摘要 3
中文摘要 5
第一章 文獻背景與研究目標 7
第一節 緒論 8
第二節 背景文獻分析 9
一. 腸病毒之特性分析 9
二. 疫苗發展 21
第三節 研究目標 29
第二章 INFECTIOUS CLONE的構築與感染機轉分析 30
第一節 緒言 31
第二節 實驗材料和方法 32
一. 材料 32
二. 實驗方法: 35
第三節 實驗結果 48
一. 1998年台灣流行之腸病毒71型之基因體結構分析 48
二. 病毒特性 49
三. 動物模式 49
四. 蛋白質結構分析 50
五. Infectious clone 的建構 51
六. Infectious clone 的特性分析 52
七. 5’UTR 對病毒毒力因子之影響 54
八. VP1蛋白質的 N 端Helix-Turn 結構對病毒株的影響 54
第四節 討論 58
第三章 疫苗的發展 66
第一節 緒言 67
第二節 材料與方法 68
一.材料 68
二.實驗方法 69
第三節 實驗結果 75
一. 質體的構築與VP1蛋白質的表現 75
二. 抗體的產生與亞型分析 75
三. Th細胞的增殖 76
四. 腸病毒71型專一性T細胞產生的細胞激素 77
五. 致死病毒挑戰試驗 77
第四節 討論 79
參考文獻 83
圖 表 110
附 錄 164
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