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研究生:陳祖淞
研究生(外文):Chor-SiongTan
論文名稱:點帶石斑魚神經性壞死病毒准種特性研究
論文名稱(外文):Characterization of the Nervous Necrosis Virus Quasispecies Property in Orange-spotted Grouper (Epinephelus coioides)
指導教授:陳宗嶽
指導教授(外文):Tzong-Yueh Tan
學位類別:碩士
校院名稱:國立成功大學
系所名稱:生物科技研究所碩博士班
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:英文
論文頁數:101
中文關鍵詞:點帶石斑魚神經性壞死病毒病毒准種特性
外文關鍵詞:Epinephelus coioidesNervous Necrosis Virus (NNV)Viral Quasispecies
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神經懷死病毒 (NNV) 對於石斑魚養殖業造成了嚴重危害。經過觀察,我們發現到神經懷死病毒感染中有一部分魚只成功生存下來成爲病毒的帶原。在近期的研究發現,病毒准種特性 (Quasispecies) 能導致病毒族群裏可能有存有一些突變後的亞種。因此,本實驗想透過不同准種的病毒外殼蛋白以了解其特性。透過病毒序列訂序,我們發現到病毒帶原石斑魚所分離到的病毒株有准種特性。在實驗當中,我們成功分離了六個不同的病毒的外殼蛋白,其中准種3與4號發現在細胞核仁定位訊號 (NoLS) 附近突變成Arginine氨基酸及在魚鰭細胞 (GF-1) 內發現有較高分佈于核與核仁內。透過流式細胞儀分析細胞周期,我們發現到神經性懷死病毒外殼蛋白有導致細胞周期停滯與G2,尤其准種2,5號擁有最明顯的差異。在分析病毒與宿主免疫相關的關係,我們發現病毒外殼蛋白會抑制腫瘤壞死因子基因 (TNF) 啟動子 的啓動,並有不同的調控強度,尤其准種2,3,4號擁有最明顯的差異。總的來說,這研究證實了神經壞死病毒存有准種的特性,並且有著不同的特性。
In grouper cultivation industry, nervous necrosis virus (NNV) infection had cause serious lose for the grouper cultivation industry. However, some of the NNV infected fishes were found survive and become a healthy NNV carrier grouper. This could be most probable due to virus quasispecies characteristic. Therefore, I would like to investigate the influence of different quasispecies of NNV coat protein (CP) on diverse aspects of nodavirus-induced pathogenesis. The chromatograph from the direct sequencing result shows that the NNV isolated from healthy NNV carrier showed more than one NNV variant present in the host. Next, series passage of NNV in grouper fin-1 (GF-1) cells also confirmed NNV quasispecies phenomena. Six CP expression plasmids from different NNV quasispecies variants were constructed. From the transient expression of CP in GF-1, it was found that QS3 and QS4 have a higher localization ratio of CP in nucleolus. Next, the result of cell cycle by using flow analysis shown that the proportion of GF-1 cells arrested in G2 transfected with pZsYellow1-N1/CP was slightly higher than that of cells transfected with blank plasmid, especially for nodavirus QS2 and QS5 CP. Next, we found that different nodavirus genotype NNV quasispecies CP downregulated the tumor necrosis factor (TNF) promoter activity especially QS2, QS3 and QS4 CP. Overall, the study represents a first comprehensive analysis of the pathogenesis of different nodavirus quasispecies CP of nodavirus.
Abstract.................................................................................................................I
Chinese Abstract................................................................................................III
Acknowledgement..............................................................................................IV
Table Contents...................................................................................................VI
Contents of Figures, Tables, and Additional Figures.......................................X
Table of Abbreviations...................................................................................XIII
Research Background..........................................................................................1
1. Grouper (Epinephelus spp.)................................................................................1
2. Nervous Necrosis Virus (NNV)....................................................................... ..2
3. Nervous Necrosis Virus Coat Protein, RNA2.................................................. ..3
4. Nucleolus Localization Signal Peptide in NNV Coat Protein............................4
5. Viral Quasispecies..............................................................................................6
6. The Current Available Methods to Detect Viral Quasispecies Population........7
7. The Selective Forces for Viral Quasispecies Population in Different
Environment Condition......................................................................................9
8. The Relationship Between Virus Quasispecies with Host Immune Response.11
9. Virus Regulating Host Cell Cycle.....................................................................11
10. Research Objective.........................................................................................12
Materials and Methods......................................................................................14
1. Materials...........................................................................................................14
(1.) Biomaterial................................................................................................ 14
(2.) Constructed Plasmid................................................................................ 14
(3.) Reaction Reagent Kit................................................................................. 16
(4.) Self-blended Buffers and Chemicals......................................................... 16
(5.) Others Chemical........................................................................................18
2. Methods............................................................................................................19
(1.) RNA Extraction.........................................................................................19
(2.) Reverse Transcription Polymerase Chain Reaction, RT-PCR...................20
(3.) Electrophoresis...........................................................................................20
(4.) Gel Extraction............................................................................................21
(5.) Competent Cells.........................................................................................22
(6.) TA Cloning................................................................................................22
(7.) Transformation..........................................................................................23
(8.) NNV Coat Protein NoLS Truncate and Point Mutation Construct...........23
(9.) Small Quantity Plasmid DNA Miniprep Extraction..................................24
(10.) High Quantity Plasmid DNA Midiprep Extraction.................................25
(11.) Nucleotide Direct Sequencing and Chromatograph Analysis.................26
(12.) Immunohistochemistry............................................................................27
(13.) GF-1 Cell Tissue Culture.........................................................................28
(14.) Cryopreserve GF-1 Cell...........................................................................28
(15.) Cell Transfection..................................................................................... 29
(16.) Microscope Slide Sample Preparation.....................................................30 (17.) Flow Cytometry Analysis........................................................................30
(18.) Construction of Tumor Necrosis Factor Gene Promoter Reporter Gene.31
(19.) Reporter Plasmid Luciferase Assay.........................................................32
(20.) Virus Infection.........................................................................................32
(21.) Virus Particle Purification.......................................................................33
Results.................................................................................................................34
1. Nervous Necrosis Virus Persistence Infection in Grouper Fish..................... 34
2. Nervous Necrosis Virus has Viral Quasispecies Characteristic..................... 35
3. Nervous Necrosis Virus Population Changes after Series Passage in GF-1
Cell culture....................................................................................................... 36
4. The Presences of Nucleolus Localization Signal (NoLS) in NNV Coat Protein.............................................................................................................. 37
5. The Six Isolated NNV Quasispecies RNA2 Variants Having Different Sequences.........................................................................................................38
6. The Localization Ratio of Different NNV Quasispecies Coat Protein............39
7. NNV Quasispecies Coat Protein Arrest Cell Cycle at G2 Phase.....................41
8. The Different NNV Quasispecies Coat Protein Downregulated Tumor Necrosis Factor (TNF) Promoter.................................................................... 42
Discussion............................................................................................................43
1. The Pathological Condition and NNV Quasispecies Population for the NNV Carrier and NNV Outbreak Grouper...............................................................43
2. Low Genetic Diversity of NNV Population Isolated from Different Infected Grouper Individual..........................................................................................45
3. Series Passage of NNV within Grouper Fin Cell Line (GF-1) Influence the NNV Quasispecies Variant Population...........................................................46
4. The Functional Nucleolus Localization Signal (NoLS) Peptide of the Nodavirus Assist Coat Protein Localization into the Nucleolus.....................47
5. The Consequences of Quasispecies Variant NNV QS3 CP and QS4 CP has an Extra Arginine Amino Acid Substitution on the NoLS Region......................49
6. The Different Extend of TNF Promoter Activity and Host Cell Cycle Affected by Different NNV Quasispecies Variant.........................................................50
7. The Future Prospects for the Nodavirus Quasispecies Research.....................52
References...........................................................................................................56
Figures, Tables, and Additional Figures..........................................................69
Personal Details................................................................................................101
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