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作者(中文):鍾心語
作者(外文):Chung, Hsin-Yu
論文名稱(中文):探討胃幽門螺旋桿菌26695脂多醣生合成及毒素因子缺失之外膜囊泡特性和致病性
論文名稱(外文):Functional characterization and pathogenicity of outer membrane vesicles isolated from Helicobacter pylori 26695 mutants defective in HP0859, CagA or VacA production
指導教授(中文):高茂傑
指導教授(外文):Kao, Mou-Chieh
口試委員(中文):張晃猷
藍忠昱
口試委員(外文):Huang-Yu Chang
Chung-Yu Lan
學位類別:碩士
校院名稱:國立清華大學
系所名稱:分子醫學研究所
學號:101080548
出版年(民國):103
畢業學年度:102
語文別:英文
論文頁數:64
中文關鍵詞:Helicobacter pyloriouter membrane vesicles
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胃幽門螺旋桿菌為一種螺旋狀的革蘭氏陰性微好氧菌,主要定殖在人類胃黏膜的上皮細胞,約一半以上的人口已感染,並且被認為是會導致人類胃部疾病的危險因子。脂多醣(Lipopolysaccharides)是一個複雜的分子,可分為三部分包含脂質A(lipid A)、核寡糖(core polysaccharide)和O抗原(O-antigen),並能誘發寄主免疫反應。外膜囊泡(outer membrane vesicles)會從菌體的外膜表面持續地釋放,其表面富含脂多醣,且已經被提出與細菌定殖存活和致病機制有關。在胃幽門螺旋桿菌中主要的兩種毒素因子為cytotoxin associated gene A protein (CagA) 和 vacuolating cytotoxin A (VacA),這兩種毒素有其個別的感染途徑和致病機制。先前我們指出hp0859的基因產物參與了ADP-L-glycero-D-manno-heptose 的生合其為建構成胃幽門螺旋桿菌脂多醣內核寡糖重要的酵素。為了要了解脂多醣結構和外膜囊泡形成的關係,及其對外膜囊泡所攜帶毒素因子CagA和VacA含量的影響,我們建構了ΔCagA、ΔVacA、ΔHP0859和ΔCagA/ΔVacA的突變菌株。在本篇的研究中,我們探討了胃幽門螺旋桿菌外膜囊泡的產量,並發現其在菌生長的不同階段不斷釋出,且在死亡期的早期達到最大值。出人意料的是野生型菌株所分泌的外膜囊泡含有兩個主要毒素CagA和VacA,但在HP0859基因缺失突變菌株所分泌的囊泡中卻顯著減少。此外,實驗的結果顯示CagA蛋白與囊泡的結合相對較弱,而VacA蛋白與囊泡的結合較強,甚至可能插入膜中或者位於囊泡的腔室內。我們也發現當人類為癌細胞株AGS細胞受到菌株所分泌的外膜囊泡感染時,囊泡主要是透過clathrin-mediated的內吞作用進入到細胞內,並造成細胞存活率顯著下降。有趣的是,當細胞受到ΔHP0859突變菌株所分泌的外膜囊泡感染時,細胞毒殺性卻顯著降低。我們確認了胃幽門螺旋桿菌所分泌的外膜囊泡有助於其感染及致病性,且提出脂多醣結構和外膜囊泡的形成及發病機制有關。
中文摘要……………………………………………………………………………. Ⅰ
Abstract…………………………………………………………………………….. Ⅱ
Table of contents…………………………………………………………………… Ⅳ
List of table…………………………………………………………………………. Ⅵ
List of figures……………………………………………………………………….. Ⅶ
List of appendixes………………………………………………………………….. Ⅷ
Abbreviations………………………………………………………………………. Ⅸ
Chapter 1 Introduction
1.1 The discovery and genetics of infectious agent, Helicobacter pylori………... 1
1.2 The characteristics of H. pylori and the treatment of this pathogen………….. 2
1.3 Infectious process and expression of toxin during H. pylori infection……….. 3
1.4 Lipopolysaccharide (LPS)……………………………………………………. 4
1.5 Two major virulence factors of H. pylori, CagA and VacA………………….. 6
1.6 The outer membrane vesicles (OMVs) of H. pylori………………………….. 10
1.7 The motivation of this study and experimental designs……………………… 11
Chapter 2 Materials and methods
2.1 H. pylori strains, plasmids and culture conditions……………………………. 13
2.2 Isolation of outer membrane vesicles (OMVs)……………………………….. 13
2.3 Imaging of OMVs isolated from H. pylori with scanning electron microscopy………………………………………………………………………...
14
2.4 Outer membrane vesicle production assay…………………………………… 15
2.5 Growth curve analysis of H. pylori…………………………………………… 15
2.6 SDS-PAGE and immune-blotting analysis…………………………………… 16
2.7 Dissociation assay…………………………………………………………….. 17
2.8 Cell culture……………………………………………………………………. 17

2.9 Preparation of total cell lysate from AGS cells co-cultured with various H. pylori outer membrane vesicles…………………………………………………...
18
2.10 Fluorescent Labeling of OMVs……………………………………………... 18
2.11 Confocal Microscopy………………………………………………………... 19
2.12 Flow cytometry Analysis……………………………………………………. 19
2.13 Evaluating cells viability with MTT assay………………………………….. 20
2.14 Statistics analysis……………………………………………………………. 21
Chapter 3 Results
3.1 Characterization and identification of outer membrane vesicles from H. pylori 26695 strain...................................................................................................
22
3.2 Bacterial growth and virulence factor analysis of OMVs derived from various virulence factor knockout mutants of H. pylori..........................................
23
3.3 The association of key virulence factors with H. pylori OMVs........................ 24
3.4 The adherence and internalization of H. pylori OMVs to AGS cells................ 25
3.5 The OMVs of H. pylori wild type are internalized via endocytosis.................. 27
3.6 The accumulation of CagA and VacA in the whole cell extract of AGS cells after co-incubation with OMVs...............................................................................
28
3.7 H. pylori OMVs may contribute to the pathology associated with H. pylori infection…………………………………………………………………………...
29
Chapter 4 Discussions……………………………………………………………… 32
Chapter 5 References……………………………………………………………… 37
Table..……………………………………………………………………………….. 48
Figures……………………………………………………………………………… 49
Appendixes…………………………………………………………………………. 63
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