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系統識別號 U0026-3107201413295600
論文名稱(中文) 幽門桿菌游動能力於致病力上的角色及其調控機制
論文名稱(英文) Roles of Helicobacter pylori motility in pathogenesis and its regulatory mechanism
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 102
學期 2
出版年 103
研究生(中文) 高正彥
研究生(英文) Cheng-Yen Kao
學號 s58981117
學位類別 博士
語文別 英文
論文頁數 112頁
口試委員 指導教授-吳俊忠
召集委員-許博翔
召集委員-鄧景浩
口試委員-何漣漪
口試委員-張玲麗
口試委員-陳亞雷
中文關鍵字 幽門桿菌  游動能力  鞭毛  病理指數  CsrA蛋白 
英文關鍵字 H. pylori  Motility  Flagella  Pathological parameter  CsrA 
學科別分類
中文摘要 胃幽門螺旋桿菌利用鞭毛產生的游動能力對於菌體進入人體後接近胃表皮層扮演重要的角色,進一步菌體可以利用黏附因子SabA與宿主發炎細胞所表現的sialyl-Lex作用而導致持續性感染。先前的研究指出CsrA蛋白參與調控幽門桿菌游動能力並進一步影響感染小鼠的能力,但是其調控機制仍不清楚。在本研究中的第一部分,將釐清菌體游動能力、SabA-sialyl-Lex的交互作用與胃部病理變化的關聯性。針對96株臨床菌株進行菌體游動能力分析,並且以西方轉漬法分析其SabA蛋白的表現。結果顯示菌體的平均游動能力為17 mm,其中8株菌株 (8.3%) 帶有較低的游動能力且游動圈直徑小於5 mm。分析受幽門桿菌感染的病人胃部檢體內菌落密度、sialyl-Lex表現、發炎指數以及疾病與菌體游動能力之關聯性。結果顯示當病人感染高游動能力的菌株,cardia位置的菌落量、body位置的急性發炎指數以及gastric atrophy的比例都有顯著性的增加 (p = 0.023、< 0.001以及 < 0.001)。當病人胃部表現sialyl-Lex抗原且感染SabA蛋白陽性、高游動能力的菌株時,總發炎指數 (包含急性以及慢性發炎) 以及菌體總菌落量都有顯著性的增加 (p = 0.016、< 0.01以及0.005)。這些結果顯示病人感染高游動能力的幽門桿菌會導致較嚴重的病理變化,並且SabA-sialyl-Lex 之間的作用對於高游動能力的菌株毒力有加乘的效果。本研究的第二個部分,釐清了CsrA調控幽門桿菌J99菌株游動能力的機制。相較於野生株J99,csrA突變的菌株喪失游動能力並且有較低的細胞黏附能力 (p < 0.001 以及 = 0.006),且csrA回補株可以回復至野生株的游動力以及感染黏附能力。利用穿透式電子顯微鏡觀察菌體的型態以及鞭毛的結構也顯示csrA突變株缺少了鞭毛的結構。進一步利用即時定量RT-PCR以及西方轉漬法分析鞭毛中的主要兩個結構蛋白flaA/flaB的表現,結果顯示相較於野生株,csrA突變株中的flaA mRNA表現量為野生株的40%,而flaB mRNA表現量為野生株的16% (p < 0.01 以及< 0.001);西方轉漬法分析的結果也發現FlaA/FlaB的蛋白在csrA突變株有顯著性的下降。此外,在csrA突變株中的rpoN mRNA相較於野生珠也下降了48%,但是rpoN mRNA的分解速度並沒有顯著性的差異。這些結果顯示CsrA蛋白可以藉由調控sigma factor rpoN的表現而影響幽門桿菌鞭毛的形成,並進一步影響菌體游動能力以及黏附能力。總結來說,幽門桿菌菌體的游動能力與感染後病理變化呈現正相關性,而CsrA可以透過調控J99菌株鞭毛的形成影響菌體的游動能力。
英文摘要 Motility mediated by the flagella of H. pylori is important for the cells to move toward the gastric mucus in niches adjacent to the epithelium, then H. pylori uses the adhesin SabA to interact with sialyl-Lex on inflammatory host cells for persistent infection. Previous studies indicated that CsrA was necessary for H. pylori full motility and mouse-infection ability, but its regulatory mechanism is still unclear. In the first part of this study, the clinical association of bacterial motility, SabA-sialyl-Lex interaction, and pathological outcomes was investigated. Ninety-six clinical isolates were screened for bacterial motility, and the expression of SabA of each isolate was confirmed by western blot. The mean diameter in the motility assay was 17 mm, and 8 (8.3%) of the isolates had impaired motility, with a diameter less than 5 mm. H. pylori infected patients were assessed for their bacterial density, sialyl-Lex expression, inflammatory scores and clinical diseases. The results showed that H. pylori density in cardia, the acute inflammatory score in the body locus, and the prevalence rate of gastric atrophy were increased in patients infected with higher motility strains (p = 0.023, < 0.001, or < 0.001, respectively). The total inflammatory scores (both acute and chronic) and bacterial density dramatically increased in patients expressing the sialyl-Lex antigen and infected with higher motility, SabA-positive H. pylori (p = 0.016, 0.01, or 0.005, respectively). These results suggest the higher motility of H. pylori enhances pathological outcomes, and the SabA-sialyl-Lex interaction has a synergistic effect on virulence of the higher motility strains. In the second part of this study, the molecular mechanism of CsrA regulatory system in H. pylori flagella formation was clarified. The csrA mutant showed loss of motility and 69% of adhesion compared to the wild-type J99 (p < 0.001 and = 0.006, respectively), and the revertant restored its motility and adhesion. The bacterial shape and flagellar structure were evaluated by transmission electron microscopy and the results showed csrA mutant was not flagellated. The expression of two major flagellins flaA/flaB and alternative sigma factor rpoN (σ54) were determined by quantitative RT-PCR and western blot. There were only 40% of flaA and 16% of flaB mRNA transcription in the csrA mutant (p < 0.01 and < 0.001, respectively), and the western blot analysis showed dramatically reduced FlaA/FlaB in the outer membrane protein of csrA mutant. The disruption of csrA also leaded to 48% decreased expression of rpoN, but the degradation rate of rpoN mRNA was not changed in the csrA mutant. These results suggest that CsrA regulates H. pylori flagella formation through controlling the expression of sigma factor rpoN, and thus affects bacterial motility and adhesion. In conclusion, the motility of H. pylori is positively correlated with pathological outcomes, and CsrA regulates H. pylori motility and flagella formation.
論文目次 中文摘要 i
Abstract iii
Acknowledgement vi
Table of contents vii
List of tables and figures ix
1. Introduction
1.1 The characteristics of H. pylori 1
1.2 The epidemiological investigation of H. pylori 2
1.3 Virulence factors of H. pylori 3
1.4 The expression of Lewis antigen in human 16
1.5 The progress of H. pylori pathogenesis 17
1.6 Regulation of flagella formation in H. pylori 19
1.7 The characteristics of CsrA protein 21
1.8 Aims of this study 28
2. Materials and methods
2.1 Bacterial strains and growth conditions 30
2.2 Cell line and cell culture 31
2.3 Analysis of bacterial growth curve 31
2.4 Motility assay 31
2.5 Bacterial adhesion and cellular il-8 gene expression assay 32
2.6 Transmission electron microscopy (TEM) 33
2.7 H. pylori-related histology 34
2.8 Immunohistochemical staining for gastric sialyl-Lex antigen 35
2.9 Extraction of bacterial DNA 36
2.10 Polymerase chain reaction (PCR) 37
2.11 Agarose gel electrophoresis 38
2.12 DNA sequencing 38
2.13 Construction of csrA and rpoN mutant and revertant strains 39
2.14 Extraction of total RNA from H. pylori 42
2.15 Reverse transcription polymerase chain reaction (RT-PCR) 43
2.16 Real-time quantitative RT-PCR (RT-qPCR) 44
2.17 RNA degradation assay 44
2.18 Induction and purification of recombinant protein 45
2.19 Production of mouse anti-FlaA, FlaB and RpoN antisera 46
2.20 Fractionation of H. pylori protein 46
2.21 Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) 47
2.22 Western blotting 48
2.23 Secondary structure prediction for rpoN RNA 50
2.24 Statistics 50
3. Results
3.1 Motility in the clinical H. pylori isolates 51
3.2 Higher motility enhances bacterial density and inflammation in the body locus 51
3.3 Higher motility enhances SabA-sialyl-Lex interaction for inflammation 52
3.4 Construction of csrA mutant and revertant 53
3.5 Roles of CsrA in H. pylori motility and infection ability 54
3.6 Examination of the flagellar structure by TEM 56
3.7 RT-qPCR and western blot analysis for flagellin expression 56
3.8 RpoN involved in CsrA regulation in J99 57
3.9 rpoN mRNA stability was not controlled by CsrA 58
3.10 Strain-specific nature of the CsrA regulatory system 59
4. Discussion
4.1 Correlation of H. pylori motility, SabA-sialyl-Lex interaction and pathological outcomes 61
4.2 CsrA regulatory system in H. pylori J99 motility 65
5. References 70
6. Tables 83
7. Figures 90
8. Appendix 106
9. Curriculum vitae 111
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