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研究生:張式欣
研究生(外文):Shih-Shin Chang
論文名稱:利用RNAi抑制EB病毒溶裂期之進行
論文名稱(外文):Inhibition of Epstein-Barr Virus Lytic Cycle by RNA Interference
指導教授:蔡錦華蔡錦華引用關係
指導教授(外文):Ching-Hua Tsai
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:微生物學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:51
中文關鍵詞:溶裂期抑制
外文關鍵詞:EBVsiRNAlytic cycle
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EB病毒與其他人類皰疹病毒科成員一樣具有兩種不同型態的生活史,包括潛伏期與溶裂期。然而於體外模式中,某些化學藥劑或細胞激素(例如:TPA:12-O-tetradecanoylphorbol-13-acetate、SB:n-sodium butyrate或是TGF-��1等)可能可以誘發EB病毒進入溶裂期。於體內模式,EB病毒在健康人體中主要維持潛伏期狀態。值得注意的是,因為EB病毒相關疾病的病患血清中常常可觀察到較高力價的抗EB病毒溶裂期基因產物抗體,表示EB病毒溶裂期的進行曾發生於相關病患體中。這顯示出EB病毒溶裂期可能在疾病的發生上扮演某種角色。在本論文中我們試圖利用RNAi方法以防止EB病毒溶裂期之進行。針對溶裂極早期基因Zta設計出具專一性的siRNA(siZ1)。於本實驗中測試siZ1對EB病毒溶裂期之影響。首先,於293細胞株中經由短期轉染實驗證明siZ1可以專一並有效地抑制Zta蛋白表現。於感染有EB病毒的細胞株中,藉由北方墨點分析法得知,siZ1能有效降低TPA/SB或是Rta轉染所誘發之Zta和Rta/Zta bicistronic mRNA表現。再以西方墨點分析法更進一步探查病毒蛋白質表現,同樣可以觀察到siZ1對EB病毒溶裂期基因表現的抑制現象。另外,實驗室從經Akata品系EB病毒感染後的293表皮細胞株中挑選出幾個能自發性進入溶裂期的細胞分株。利用siZ1也能有效抑制這些細胞分株內自發性病毒溶裂期之進行。
由於Rta和Zta蛋白質表現後會互相調控,所以不易單獨探討Rta或Zta所調控的病毒基因。藉由使用siZ1,我們探討Rta可能調節的病毒基因。以Rta轉染誘發病毒細胞株進入溶裂期,再同時以siZ1抑制內生性Zta蛋白質的表現,缺乏Zta的狀態下,Rta蛋白質仍然可以轉活化BALF2、BGLF4、BGLF5、BHRF1、以及(VCA,gp125)等溶裂基因。於本論文中,首次證明RNAi可以有效應用於抑制EB病毒溶裂期之進行。未來在探討EB病毒基因弁鄋漪膍s上,RNAi可能是一個很好的方法。
此外,本論文也試圖探討EB病毒經誘發而進入溶裂期所需要的細胞因子。先前釵h對EB病毒相關疾病的研究觀察到,細胞內p53蛋白質多量累積於受EB病毒感染的組織細胞中。而同時,在這些疾病患者的血清又常可偵測到較高力價的抗EB病毒溶裂期產物抗體。因此我們欲探討p53對EB病毒溶裂期誘發的重要性。本實驗發現,利用RNAi抑制NA細胞株(感染EB病毒的鼻咽癌細胞株)的p53表現後,利用西方墨點分析法證明NA細胞株無法再受TPA/SB誘發而進入溶裂期。利用PFT(p53抑制劑)處理過的NA細胞株也同樣無法受TPA/SB的誘發。有趣的是,降低p53表現或以PFT抑制p53弁鄖瓣ˉv響由轉染Zta或Rta所誘發的病毒溶裂期。本實驗顯示出p53在目前測試過的細胞株中,很可能是EB病毒進入溶裂期的必備因子。這也為p53蛋白於病毒與寄主交互關係中提供了一個嶄新的視野。
EBV(Epstein-Barr virus), like other human herpesviruses, possesses two phases in its life cycle: latent and lytic stages. In vitro, however, EBV can be triggered into lytic cycle in the presence of the chemicals or cytokines, such as 12-O-tetradecanoyl -phorbol-13-acetate(TPA), n-sodium butyrate(SB), or TGF-��1. In vivo, EBV mainly maintains latency in healthy carrier. Of note, EBV is reactivated into lytic cycle in individual with EBV-associated diseases, by the evidence of high titer antibodies against the EBV lytic products. It seems that EBV reactivation may play some role in the development of diseases. In this study, we tried to use RNA interference(RNAi) approach to prevent EBV lytic cycle progression. siRNA(siZ1) against the immediate early gene Zta was designed and used in the experiments. Firstly, the specificity of the siZ1 was tested by its ability to specifically knock down Zta expression in 293 cells in transient-transfection assay. In EBV-carrying cells, it was demonstrated by northern blot analysis that siZ1 effectively decreased expression of Zta and Rta/Zta bicistronic mRNA, no matter cells were chemically-activated by TPA/SB or triggered by Rta-transfection. The inhibitory phenomenon was also observed at the protein level by western blotting analysis. The inhibition of EBV lytic cycle progression caused by siZ1 was also demonstrated in spontaneous EBV-producing epithelial cell lines, which were established in our lab by infecting 293 cells with recombinant Akata EBV.
Using siZ1 approach, we also explore the possibility to reveal the genes regulated by Rta. It is difficult to dissect whether the viral genes are regulated by Zta or Rta since they are reciprocally regulated by each other. By use of siZ1 to specifically knock down Zta expression in EBV-carrying cells transfected with Rta expression plasmid, it was shown that Rta still can transactivate the expression of BALF2, BGLF4, BGLF5, BHRF1 and VCA(gp125) genes. In this study, we provided evidence that RNAi can be effectively used in preventing EBV from lytic progression and in investigating the function of viral genes.
In another aspect, we were attempting to investigate which cellular factor is required for lytic EBV induction. It was reported that p53 protein accumulation occurs in some EBV-infected tissue cells, meanwhile, high titer antibodies against EBV lytic products are also observed in those patients’ sera. Hence, we tried to elucidate the roles of p53 in the EBV lytic induction. After knocking down p53 expression by RNAi in NA cells, an NPC cell line infected with Akata EBV, data from western blot analysis showed that EBV can no longer be induced into lytic cycle while treated with TPA/SB. The essential role of p53 for EBV lytic cycle progression can be further demonstrated by the PFT(a p53 inhibitor). Western blot analysis indicated that PFT pretreatment also abolishes the TPA/SB-stimulated lytic induction in NA cells. However, it is of interest that exogenous Zta or Rta-transfection can still promote the lytic cycle progression in the presence of PFT. Our report strongly suggests that p53 may be an essential factor for EBV lytic induction in the tested cell lines, and it provides a new insight into the role of p53 in virus-host interaction.
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