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系統識別號 U0026-2207201516154700
論文名稱(中文) 幽門桿菌菌株特異性於碳源調節蛋白調控游動能力之研究
論文名稱(英文) The study of strain-specific CsrA-regulatory system in controlling Helicobacter pylori motility
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 103
學期 2
出版年 104
研究生(中文) 黃意婷
研究生(英文) Yi-Ting Huang
學號 T36024110
學位類別 碩士
語文別 英文
論文頁數 81頁
口試委員 指導教授-吳俊忠
口試委員-何漣漪
口試委員-鄧景浩
口試委員-張玲麗
中文關鍵字 幽門桿菌  游動性  碳源調節蛋白  鞭毛結構 
英文關鍵字 Helicobacter pylori  motility  CsrA  flagellar structure 
學科別分類
中文摘要 幽門桿菌 (Helicobacter pylori) 是常見的人類致病菌,全球人口約有50 %為幽門桿菌之帶原者,而感染後會增加罹患胃部疾病甚至是發展成胃癌的風險。鞭毛結構產生之游動能力已證實為重要的毒力因子,可以幫助幽門桿菌成功貼附於人體的胃黏膜並進行拓殖(colonization)。而幽門桿菌之所以能在胃部嚴苛的環境中生存,碳源調節蛋白 (Carbon storage regulator A,CsrA) 即為重要的調控因子之一。在過去的研究中證實CsrA為全面性的調節蛋白,會調控幽門桿菌的游動性和動物感染能力。在實驗室先前的研究證實標準菌株J99和26695之csrA突變株的游動能力皆會顯著性下降,然而在調控基因的轉錄和轉譯層次具有菌株特異性,因此我的研究目的為了解其中造成菌株特異性的機制。首先,我們利用電子顯微鏡觀察到J99和26695*之csrA突變株都沒有鞭毛結構的存在,顯示出游動能力的喪失導因於鞭毛的生合成受到抑制。接著探討鞭毛生合成基因的轉錄層次,我們發現J99之csrA突變株其flaA, flaB, rpoN之mRNA皆有顯著性下降,表現量分別為野生株的57%, 29%, 57%。而26695*之csrA突變株其flaB, rpoN之mRNA也呈現顯著性下降,但是在flaA (major flagellin)的mRNA表現量則呈現顯著性的上升,其flaA, flaB, rpoN之mRNA表現量分別為210%, 57%, 59%。結合實驗室先前的研究,於幽門桿菌J99其CsrA主要會透過Class I 鞭毛生合成基因 (σ54) 進而調控下游Class II (flaB, flgE, flgK, flgL, flgM, fliA)與Class III (flaA) 基因。在我的研究中,幽門桿菌26695*其CsrA也會透過相同的路徑,透過σ54去調控Class II (flaB) 鞭毛基因的表現,然而有趣的是在Class III (flaA, omp11, envA)基因的表達量呈現顯著性增加的趨勢。於轉譯層次,我們發現J99之csrA突變株其FlaA/FlaB的鞭毛蛋白的合成量有顯著性下降,但是26695*之csrA突變株其FlaA與FlaB表現量並沒有差異與下降的趨勢,和J99之csrA突變株相比仍具有鞭毛蛋白的表現。最後,我們認為RpoN可能在CsrA調控游動能力之路徑中扮演重要的角色。我們發現J99之rpoN 突變株其flaA的mRNA表現量與csrA突變株相比,flaA下降的趨勢更為顯著。而26695*之rpoN 突變株其flaA的mRNA表現量相較於csrA突變株,則呈現更加顯著的上升趨勢。總結以上結果,我們發現CsrA蛋白可以藉由調控rpoN (σ54) 的表現量而影響幽門桿菌鞭毛的生合成,進而影響菌體的游動能力。此外,rpoN (σ54) 是CsrA蛋白調控幽門桿菌游動能力具有菌株特異性的關鍵基因。
英文摘要 Helicobacter pylori infects 50% of the population worldwide, and increases the risk for developing peptic and duodenal ulcer, gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma (MALToma). Polar flagella, the important virulence factor of H. pylori, contribute to colonize in human stomach mucosa persistently. Previous studies indicated that carbon storage regulator A (CsrA) was necessary for H. pylori full motility and infection ability. We have demonstrated previously that H. pylori strains J99 and 26695 in csrA mutants were deficient in motility. However, the mechanism of CsrA in these strains to cause the deficient motility was different. Therefore, the aim of this study was to understand the mechanism causing strain-specific CsrA-regulatory system in controlling H. pylori motility. Our results demonstrated that no flagella were observed in the csrA mutants by the transmission electron micrographs compared to the wild-type strain. The transcriptional levels showed that only 57% flaA, 29% flaB and 57% rpoN (σ54) mRNA expression in the csrA mutant J99 (p < 0.001, < 0.001 and < 0.01, respectively). Interestingly, It showed 210% flaA, 57% flaB and 59% rpoN (σ54) mRNA expression in the csrA mutant 26695* (p < 0.01, < 0.05 and < 0.01, respectively). In H. pylori J99, CsrA mainly regulates class I flagellar genes (alternative sigma factor σ54) and thus governs downstream class II (flaB, flgE, flgK, flgL, flgM, fliA) and class III (flaA) flagellar genes’ expression. In common pathway, the transcriptional levels of σ54 and flaB also decreased in the csrA mutant 26695*, whereas the expression of class III (flaA, omp11, envA) flagellar genes increased. In addition, the FlaA and FlaB proteins were decreased in the csrA mutant J99, whereas FlaA protein was no such change in the csrA mutant 26695*. Finally, we evaluated the role of RpoN participated in the CsrA-regulatory system. The flaA mRNA expression decreased more prominent in the rpoN mutant J99, whereas flaA mRNA expression dramatically increased in the rpoN mutant 26695*. Based on my results, the strain-specific nature of the CsrA-regulatory system is suggested to be a RpoN-dependent pathway.
論文目次 中文摘要 i
Abstract iii
Acknowledgements v
Table of contents vi
List of tables and figures ix
1. Introduction 1
1.1 The history of Helicobacter pylori 1
1.2 The characteristics of H. pylori 1
1.3 The epidemiological investigation of H. pylori 2
1.4 Virulence factors of H. pylori 3
1.4.1 Urease 3
1.4.2 Flagella and motility 5
1.4.3 Adhesins 5
1.4.4 The cag pathogenicity island (cag-PAI) 6
1.4.5 Vacuolating cytotoxin A (VacA) 8
1.5 The progress of H. pylori pathogenesis 9
1.6 Regulation of flagella formation in H. pylori 10
1.7 Carbon storage regulator A, CsrA 11
1.7.1 The structure of CsrA 11
1.7.2 Post-transcriptional regulation of CsrA 12
1.7.3 CsrA functions as global regulator 13
1.8 Aims of the study 15
2. Materials and methods 16
2.1 Chemicals and reagents 16
2.2 Bacterial strains, plasmids and animal sources 16
2.3 Bacterial growth conditional and stoarge 16
2.4 Extraction of bacterial DNA 17
2.4.1 Extraction of plasmid DNA from E. coli 17
2.4.2 Extraction of genomic DNA from H. pylori 17
2.5 Molecular cloning 18
2.5.1 Polymerase chain reaction (PCR) 18
2.5.2 Agarose gel electrophoresis 19
2.5.3 DNA ligation 19
2.5.4 Preparation of E. coli competent cells 19
2.5.5 Transformation (heat shock) 20
2.5.6 Natural transformation of H. pylori 20
2.6 Southern blotting 21
2.6.1 The preparation of probes 21
2.6.2 Preparation of genomic DNA samples 21
2.6.3 Transfer 21
2.6.4 Hybridization 22
2.6.5 Wash and detection 22
2.6.6 Stripping 23
2.7 Soft agar motility assay 23
2.8 Analysis of bacterial growth curve 23
2.9 Transmission electron microscopy (TEM) 24
2.10 Extraction of total RNA from H. pylori 24
2.11 Reverse transcription polymerase chain reaction (RT-PCR) 25
2.12 Real-time quantitative RT-PCR (RT-qPCR) 25
2.13 Preparation of H. pylori proteins 26
2.13.1 Total protein 26
2.13.2 Fractionation 26
2.14 Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) 27
2.14.1 Preparation of SDS-PAGE 27
2.14.2 Protein quantification 27
2.14.3 Running SDS-PAGE 27
2.14.4 Staining and destaining the SDS-PAGE 28
2.15 Western blotting 28
2.15.1 Electrophoretic transfer to nitrocellulose membrane 28
2.15.2 Blocking, hydrization and detection of antigen on membrane 28
2.16 Induction and purfication of recombinant protein 29
2.16.1 Induction of recombinant protein expression 29
2.16.2 Ni+column preparation 29
2.16.3 Purification of recombinant proteins 29
2.17 Production of mouse antisera 30
2.18 Bioinformatic tools 30
2.18.1 Statistics 30
2.18.2 Sequence alignment 30
2.18.3 Secondary structure prediction for rpoN RNA 30
3. Results 31
3.1 Isolation of csrA mutant and revertant in J99/26695* 31
3.2 Confirmation of csrA mutant and revertant in J99/26695* 32
3.3 Growth curve and motility ability of wild-type, csrA mutant and revertant in J99/26695* 33
3.4 Transmission electron micrographs of negatively stained H. pylori 34
3.5 The expressions of flagellin protein, FlaA and FlaB, in wild-type, csrA mutant and revertant J99/26695* 34
3.6 The transcriptional level of flaA/flaB/rpoN in wild-type, csrA mutant and revertant J99/26695* 35
3.7 The role of RpoN involved in the strain-specific nature of CsrA-regulatory system 35
4. Discussion 37
4.1 Roles of CsrA and RpoN in H. pylori motility 37
4.2 The main reason causing deficient motility in csrA mutant 26695* 38
4.3 The strain-specific nature of CsrA-regulatory system 38
4.4 Summary 40
5. References 41
6. Tables 53
7. Figures 58
8. Appendix 74

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