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系統識別號 U0026-0812200914014224
論文名稱(中文) 利用小鼠適應株探討腸病毒71型神經毒性
論文名稱(英文) Exploration of the neurovirulence of enterovirus 71 with mouse-adapted strains
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 95
學期 2
出版年 96
研究生(中文) 王雅芳
研究生(英文) Ya-Fang Wang
電子信箱 s5890126@ccmail.ncku.edu.tw
學號 s5890126
學位類別 博士
語文別 中文
論文頁數 107頁
口試委員 指導教授-余俊強
召集委員-黎煥耀
口試委員-王貞仁
口試委員-蘇益仁
口試委員-伍安怡
口試委員-林貴香
中文關鍵字 腸病毒71型  神經毒性  小鼠適應株 
英文關鍵字 mouse-adapted strains  neurovirulence  enterovirus 71 
學科別分類
中文摘要 腸病毒71型 (EV71)是屬於小核醣核酸病毒(Picornaviridae)家族的一員。目前腸病毒71型已被醫界認為是在小兒麻痺病毒根除以後,最重要的小兒神經毒性病毒。我們將腸病毒71型臨床分離株4643以腹腔感染方式感染1日齡ICR小鼠,在小鼠腦部進行病毒繼代並分離腸病毒71型小鼠適應株。在小鼠繼代過程中發現小鼠適應株隨著繼代代數的增加,其對1日齡ICR仔鼠的毒性也隨之增加;而繼代第四代的小鼠適應株MP4對1日齡ICR仔鼠的毒性較原臨床分離株4643增強100倍(50%致死計量分別為102 和104)。將此小鼠適應株MP4以口服方式感染7日齡ICR仔鼠,發現仔鼠在感染後出現體重下降及後肢無力等症狀,並在感染後7-9天死亡;病理切片檢查發現在小鼠腦幹及脊髓有神經細胞凋亡伴隨發炎細胞的浸潤,後肢肌肉壞死,脾臟淋巴球減少,但並無肺水腫。另外,小鼠適應株MP4可經由感染周邊組織侵入中樞神經系統並在小鼠腦部繁殖,顯示小鼠繼代過程中小鼠適應株MP4病毒增強了對小鼠的神經侵入性及神經毒性。體外實驗發現小鼠適應株在生物特性與4643有很大差異,包括在病毒繁殖較快、對神經細胞毒性較強、病毒溶菌斑較大、在高溫及酸性環境較能存活等,其中溶菌斑大小、45C高溫及酸性環境耐受性與小鼠毒性有較高相關性。分析病毒散佈途徑,發現口服感染腸病毒71型後,病毒會在小腸有短暫的複製,在感染後期,脊髓、腦及肌肉則是病毒主要複製的地方。分析基因序列與臨床分離株4643的差異,發現小鼠適應株在5’-非轉譯區有4個核苷酸改變,結構蛋白共有9個,而非結構蛋白則有21個核苷酸改變,導致結構蛋白VP2與VP1各有1個胺基酸改變,非結構蛋白2A、2C及3C共有5個胺基酸上的變化。有趣的是小鼠適應株的第一代MP1就有29個核苷酸的改變,這些改變使得MP1增加了高溫及酸性環境的耐受性但對小鼠致死性影響不大;而第二代及第三代增加了5個核苷酸的改變,分別在VP3、VP1及3D,除了對高溫及酸性環境耐受度持續增加外,對小鼠致死性亦增加10倍;而至第四代MP4卻有3個核苷酸又變回原來的4643及MP1,位於2A及3D,而MP4對小鼠致死性則是最強的且也增加了神經侵犯性,可由周邊神經感染侵入中樞神經系統。為了探討IRES活性是否影響病毒毒性,我們首先建構螢火蟲螢光素酶與小鼠適應株MP4或臨床分離株4643的5’-UTR區域融合質體,結果顯示帶有小鼠適應株MP4的5’-UTR融合質體的螢光表現量在RD及SK-N-SH細胞都較原臨床分離株4643高出1.5倍。為了驗證此IRES活性是否會影響病毒在小鼠的毒性,我們建構小鼠適應株MP4及臨床分離株4643的infectious clones,並利用此infectious clones將5’-UTR,包含IRES區域的964個核苷酸進行互換,產生兩個chimera infectious clones。病毒特性分析發現4M-1 (MP4 infectious clone攜帶4643的IRES)在RD細胞能產生較大溶菌斑,且以腹腔感染1日齡仔鼠會造成小鼠死亡;而M4-1 (4643 infectious clone攜帶MP4的IRES)則產生較小溶菌斑且不會造成小鼠疾病,但病毒在RD細胞的生長卻比4M-1快,這些結果猜測腸病毒71型的5’-UTR可能影響病毒生長,但只有5’-UTR的改變可能不足以造成小鼠毒性的增加及影響病毒溶菌斑的大小。
英文摘要 Enterovirus 71 (EV71), a single positive strand RNA virus that belongs to Picornaviridae, has caused significant morbidity and mortality worldwide since it was first described in 1969 in the United States. EV71 infections usually cause epidemic HFMD and occasionally have been associated with aseptic meningitis, encephalitis and polio-like illness. The outbreak of EV71 in Taiwan in 1998 killed 78 children. It has been suggested that EV71 may become the most important neurotropic enterovirus after the eradication of poliovirus. One of the major barriers to study the pathogenesis of EV71 and vaccine development is the lack of a suitable animal model. In an attempt to establish a murine model of EV71 infection, we found that mouse-adapted EV71 strains, which were isolated from the brain of ICR neonatal mice infected intraperitoneally at the age of day 1, were more virulent than the parental strain. Furthermore, MP4 (the fourth passage of mouse-adapted EV71 strain), in contrast to its parental strain EV71/4643, could orally infect and replicate in the central nervous system of neonatal mice, indicating an increase in neuroinvasiveness of the virus after adaptation. In vitro mouse-adapted EV71 strains exhibited a more rapid growth rate, bigger plaque size, lower temperature-sensitivity and more resistant to heat treatment at 45C and acidic condition than parental strain 4643. Oral inoculation of MP4 into 7-day-old mice caused encephalitis, flaccid paralysis and death of mice at 7-9 days post infection. Pathological examination revealed inflammatory cell infiltration and neuron apoptosis in the brain and spinal cord, massive necrosis in the limb muscles and severe lymphocytes depletion in the lymphoid organs. After oral inoculation, there was an early and transient virus replication in the intestines, whereas the spinal cord, brain and muscle became the sites of viral replication during the late phase of the infection. Protection against EV71 challenge was demonstrated following administration of hyper-immune serum after inoculation of the virus. Nucleotide (nt) sequence analysis of the mouse-adapted EV71 strains genome revealed there were thirty-one nucleotide changes after four in vivo passages, resulting in five amino acid (aa) substitutions. Interestingly, MP1, the first passage of the virus, had 29 nt and 4 aa changes with increased resistant phenotypes (rct marker, thermostability and acid resistance) but not in vivo toxicity. Five additional nt changes and three aa substitutions (1 in VP1, E710Q, and 2 in 2A, V964M and A1009V) were occurred in the transition of MP1 to MP2. MP2 and MP3, the second and third passages of parental strain 4643 in vivo, were strongly acid resistance and more thermostable and lethal to 1-day-old mice than the 4643 with a LD50 of 1 log-fold decrease. MP4, the virus strain after the forth passage of 4643, was highly toxic to 1-day-old mice (2 log-fold decrease in LD50) and acquired the ability to invade the central nervous system after oral delivery. The MP4 had a total of 31 nt and 5 aa different than those of 4643, and only one aa different between MP1 and MP4 which located in the VP1 region (E710Q). Studies with the luciferase reporter plasmid demonstrated that the IRES activity of MP4 was higher than parental strain 4643 in both RD cells and SK-N-SH cells. Furthermore, the full-length infectious cDNA of 4643 and MP4 were constructed and used to generate the chimeric viruses. The 4M-1, a cDNA clone after replacing the 5’ terminal 964 nucleotides of MP4 genome with the corresponding region of the 4643 strain, produced MP4-like plaques in RD cells and showed neurovirulence similar to that of MP4 in neonatal mice, but had a kinetic of replication in RD cells similar to 4643. We concluded that, unlike poliovirus, the 5’ UTR of EV71 may be important for viral replication and that its function alone is not sufficient for large plaque phenotype and mouse virulence. We believe that both mouse-adapted EV71 strains and murine model will provide excellent frameworks for examining the pathogenesis of EV71, verifying the virulence determinants of EV71, and developing vaccines and anti-EV71 drugs.
論文目次 中文摘要 ................................................ I
英文摘要................................................III
誌謝......................................................V
目錄.....................................................VI
圖目錄...................................................IX
表目錄...................................................XI
縮寫索引................................................XII
緒論......................................................1
腸病毒71型之研究..........................................1
一、病毒學概論............................................1
二、病毒流行病學..........................................4
三、臨床表徵..............................................4
四、致病機轉..............................................5
五、病毒毒性基因研究......................................6
六、動物模式..............................................8
研究動機與實驗設計........................................9
實驗材料與方法...........................................10
A.材料...................................................10
一、實驗動物.............................................10
二、病毒株...............................................10
三、細胞株...............................................10
四、藥品與試劑...........................................10
五、耗材.................................................12
六、儀器.................................................13
B.實驗設計與方法.........................................14
一、細胞培養.............................................14
二、病毒培養與定量.......................................14
三、腸病毒71型小鼠適應株製備.............................15
四、病毒生物特性試驗.....................................16
五、小鼠感染模式.........................................18
六、小鼠體內病毒動態分布及組織病理變化...................18
七、反轉錄酵素-聚合酵素連鎖反應 (RT-PCR).................20
八、基因序列分析比對.....................................22
九、螢火蟲螢光素酶質體表現EV71 IRES活性測試..............22
十、Infectious clone質體建構.............................23
十一、5’端互換鑲嵌病毒製備..............................24
十二、單株抗體融合瘤技術.................................24
十三、膠體電泳分析 (SDS-PAGE) ...........................24
十四、西方墨點 (western blot)............................26
十五、統計分析...........................................27
結果.....................................................28
一、腸病毒71型小鼠適應株毒性隨活體內繼代次數增加而增加...28
a.小鼠適應株MP4在肌肉、神經及腸道細胞株生長較快且對神經細胞毒性亦較強...............................................28
b.小鼠適應株MP4較臨床分離株4643更容易造成腸道細胞與神經細胞細胞凋亡.................................................29
二、小鼠適應株MP4能經口服方式感染七日齡仔鼠..............29
a.小鼠適應株MP4以口服方式感染七日齡小鼠所造成之病理變化..30
b.小鼠適應株MP4以口服方式感染七日齡仔鼠後病毒在體內的動態分布.......................................................30
三、小鼠適應株MP4較臨床分離株4643增強神經侵略性及神經毒性31
四、小鼠適應株病毒生物特性與小鼠致死性的相關性...........31
五、小鼠適應株病毒基因序列分析...........................32
六、利用螢火蟲螢光素酶質體比較小鼠適應株與臨床分離株病毒5’端IRES活性...............................................33
七、建構小鼠適應株MP4及臨床分離株4643 infectious clones..34
八、建構MP4與4643 chimera病毒株 infectious clones........34
討論.....................................................36
結論.....................................................47
參考文獻.................................................48
圖附錄...................................................57
表附錄...................................................78
附圖.....................................................84
附錄.....................................................88
論文發表.................................................97
作者簡歷................................................106
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