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系統識別號 U0026-0812200912002711
論文名稱(中文) A 群鏈球菌免疫球蛋白 G 分解酶及篩選寡胜肽膜透酶相關蛋白之研究
論文名稱(英文) Characterization of immunoglobulin G degrading enzyme and screening the cellular interaction proteins with oligopeptide permease A in Group A Streptococcus
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 94
學期 2
出版年 95
研究生(中文) 陳文怡
研究生(英文) Wen-Yi Chen
學號 t3693406
學位類別 碩士
語文別 中文
論文頁數 113頁
口試委員 口試委員-蔡佩珍
口試委員-黃溫雅
口試委員-林以行
口試委員-何漣漪
指導教授-吳俊忠
中文關鍵字 酵素  免疫球蛋白G分解酶 
英文關鍵字 IdeS  immunoglobulin G degrading enzyme of streptococc 
學科別分類
中文摘要 A 群鏈球菌為一重要的人類病原菌。此菌有許多致病因子,其中免疫球蛋白 G 降解酶 (Immunoglobulin G degrading enzyme of S. pyogenes , IdeS )又稱為 Mac,能分泌至細胞外且對免疫球蛋白 G 具分解能力的的半胱胺酸蛋白酶。此蛋白酶不僅幫助細菌抑制抗體調控的吞噬作用,並且抑制在吞噬過程中所產生的活性氧分子 (Reactive oxygen species) 。為了進一步證實 IdeS 在致病機轉之角色,我們利用插入法構築 ideS 突變株。由南方墨點法及西方墨點法證實 ideS 基因已被中斷,並無法表現 IdeS,而 ideS 互補株有部分回復現象。在體外試驗,此突變株幾乎無法存活於人類全血,並且在氧化性壓力環境的生存能力與野生株相比約下降 4 倍,而 ideS 互補株有部分回復之現象。這些結果顯示 IdeS 在 A 群鏈球菌致病機轉中確實扮演著重要的角色。然而在野生株與突變株感染小鼠後,小鼠存活率沒有顯著上的差異,顯示 IdeS 在 A 群鏈球菌感染小鼠上不具其重要性。此外,本研究群先前已證實寡胜肽膜透酶在 A 群鏈球菌在感染過程扮演重要角色,為了釐清 OppA 之功能,本研究利用酵母菌雜交試驗篩選與 OppA 有相關之蛋白質。在 176 個有交互作用的轉型株中找到 100 個不同酵素片段的轉型株,將 100 個基因定序後至 NCBI 資料庫中進行比對。我們發現細胞上的蛋白質 integrin 與細胞間質蛋白質 laminin 與 OppA 可能有交互作用。未來應進一步釐清這些蛋白質與 OppA 之關連性。



英文摘要 Group A streptococcus (GAS) is an important human pathogen. There are many virulence factors located either on the bacterial surface or secreted into the surrounding environment. The immunoglobulin G-degrading enzyme (IdeS), also known as streptococcal Mac, is a secreted IgG-specific cysteine endopeptidase. IdeS not only inhibits phagocytosis, but also reduces reactive oxygen species (ROS) production during phagocytosis, suggesting that IdeS is important in the pathogenesis of GAS. To further investigate the potential roles of IdeS in the pathogenesis of GAS, an isogenic ideS mutant was constructed by integrative plasmid to disrupt the ideS and confirmed by Southern blot and Western blot. The ideS complementation strain had partially restored IdeS expression. In vitro, the ideS mutant almost can’t survive in the human whole blood. The mutant decreased 75% of ability to survive in oxidative environment, and ideS complementation strain had partially restored its ability. These results show that IdeS plays an important role in streptococcal infections. However, there was no difference of survival rate in BALB/c mice between wild-type strain and ideS mutant, suggesting that IdeS is not an important virulence factor for GAS infection in BALB/c mice. Previously, in our lab, we have demonstrated that OppA plays an important role in the pathogenesis of GAS infection. To further study the function of OppA, yeast two-hybrid assay was used to screen for interacted proteins. A total of 100 restriction patterns were found in 176 clones. One hundred clones were sequenced and compared to NCBI database. We found several interesting clones that OppA may associate with integrin (cell surface protein) and laminin (extracellular matrix glycoprotein). In the future, the interaction between OppA and these proteins needs further study.



論文目次 中文摘要……………………...……………………………………………….i
英文摘要……………………….……………………………………………..ii
誌謝..................................................................................................................iii
目錄..................................................................................................................iv
表目錄............................................................................................................viii圖目錄..............................................................................................................ix
符號與縮寫......................................................................................................xi
序論……………………………………………...……………………………1
材料與方法.....................................................................................................12
一. 菌種及動物來源……………………………………………………….12
二. 儀器與藥品.............................................................................................12
三. 細菌 DNA的抽取……………………………………………………..12
四. 細菌培養與保存.....................................................................................15
五. 洋菜膠體電泳………………………………………………………….15
六. DNA 片段回收………………………………………………………..15
七. 聚合酶連鎖反應 (Polymerase chain reaction,PCR)……….................16
八. 細細菌 RNA 的抽取……………………………………………….…16
九. RT-PCR cDNA 的製備…………………………………………….….17
十. 限制酶切割及 DNA 接合作用………………………………………17
十一. 大腸桿菌勝任細胞製備…………………………………………...18
十二. 細胞轉型作用 (Transformation)……………………..……………18
十三. 電極轉型作用(Electroporation)………………………..…………..19
十四. 南方墨漬雜交法(Southern blot hybridization)…………..………...20
十五. 北方墨點法(Northern blot hybridization)………………..………...22
十六. SDS-PAGE 蛋白質膠體電泳……………………………..………23
十七. 西方墨點法 (Western blot hybridization)…………………..……..23
十八. 蛋白質的萃取及定量……………………………………….……..24
十九. 多株抗體 (Polyclonal antibody) 的製備……………………........25
二十. 利用 ELISA 測定老鼠血清抗 IdeS 的效價………………..…...25
二十一. 生長曲線的測定……………………………………………….…..26
二十二. 殺菌能力的測定 (Bactericidal assay)…………………………..…26
二十三. A 群鏈球菌感染小鼠的模式…..…………………………..……..26
二十四. H2O2 耐受性試驗 (H2O2 challenge assay)………………………...27
二十五. β-galactosidase 濾紙試驗……………………………………….....27
結果.................................................................................................................28
第一部份: ideS 基因對 A 群鏈球菌感染過程的影響.............................28
一. 以插入法構築 ideS 與 speB 突變株………………………………..28
A. 構築 streptococcal integrational vector………………………...28
B. 以 electroporation將重組質體送入 A 群鏈球菌…...………..30
C. 以南方墨點法 (Southern blot) 確認 ideS 與 speB 突變株...31
D. 以 西方墨點法 (Western blot) 確認 ideS 與 speB 突變株...32
E. 以 RT-PCR 分析 ideS 與 speB 下游基因轉錄情形..............33
二. 構築ideS互補株 (Complementation strain)…………………………..34
A. 構築可在 A 群鏈球菌中自行複製 ideS 之質體.....................34
B. 以 electroporation 將重組質體送入 A 群鏈球菌中...............34
C. 以西方墨點法分析 ideS互補株 (SW573) IdeS 表現情形......34
三. 抗 r-IdeS 多株抗體之製備…………………………………………...35
四. 比較野生株 A20 以及 NZ131 其 IdeS 表現量............................... 35
五. 分析 speB 突變株 (SW574) ideS基因及其轉錄情形........................36
六. 比較野生株與突變株之生長曲線.........................................................36
七. 分析野生株 (NZ131) 中 ideS 轉錄情形............................................37
八. 全血殺菌能力測試 (Whole blood killing assay)....…………………...37
九. 比較野生株與 ideS 突變株對動物之致死率 (in vivo mortality)…...38
十. 比較野生株與 ideS突變株在氧化壓力環境下之生存能力
(H2O2 challenge assay)............................................................................38
第二部分:酵母菌雜交試驗篩選寡胜肽膜透酶相關蛋白之研究...............40
一. 構築可在酵母菌及大腸桿菌中複製 OppA 之質體............................41
二. 將質體 pMW414 轉型至酵母菌株 AH109.........................................41
三. 酵母菌融合試驗......................................................................................42
四. 大腸桿菌質體轉型至酵母菌..................................................................43
五. 解序結果..................................................................................................44
討論.................................................................................................................45
參考文獻.........................................................................................................54
表.....................................................................................................................63
圖.....................................................................................................................71
附錄.................................................................................................................94
表目錄

Table 1. Bacterial strains used in this study.....................................................63
Table 2. Plasmids used in this study................................................................64
Table 3. Primers used in this study..................................................................65
Table 4. Sequence results of target proteins that may interact with OppA.....67
圖目錄
Fig. 1 Schematic map of the construction of plasmids pMW383 and pMW385..............…………………………….............
71
Fig. 2 Alignment of cat cassette of pMW385 and the accession No. M35190 (cat gene)........................................................
72
Fig. 3 Restriction map of the speB gene in the wild-type strain NZ131 and its isogenic mutant...……………………….....
73
Fig. 4 Restriction map of the ideS gene in the GAS isolates (A20 and NZ131) and its isogenic mutant....................................
74
Fig. 5 Construction of the ideS isogenic mutant in A20 by double cross-over recombination and confirmed by Southern blot analysis..............................………......……..

75
Fig. 6 Southern hybridization of wild-type strain and its ideS isogenic mutants probed with 0.8 kb fragment of ideS gene...............……………………………………...............

76
Fig. 7 Southern hybridization of wild-type strain (NZ131) and speB isogenic mutant (SW574) probed with 0.7 kb fragment of speB gene…….................................................

77
Fig. 8 Western-blot analysis of IdeS and SpeB in GAS culture supernatant and proteolytic activity of speB mutant (SW574).……...............…….….........................................

78
Fig. 9 RT-PCR analysis of downstream genes of ideS (A) and speB (B)……...………………...........…………………….
79
Fig. 10 Schematic map of the construction of plasmid pMW400... 80
Fig. 11 Characterization of antibody responses to r-IdeS after immunization with r-IdeS…………………………......…..
81
Fig. 12 IdeS expression in different GAS strains.……................... 82
Fig. 13 Analyze ideS gene and ideS transcript of wild-type strain (NZ131) and speB mutant (SW574)....................................
83
Fig. 14 Growth curves of wild-type strain (NZ131) and its isogenic mutants (SW572 and SW574)...............................
84
Fig. 15 Analyze ideS transcript of wild-type strain (NZ131) in different time point by Northern blot……………………..
85
Fig. 16 Whole blood killing assay of wild-type strain and its isogenic mutants....……………………………………......
86
Fig. 17 Survival rate of S. pyogenes-infected BALB/c mice after inoculation in air pouches with 4 × 109 CFU of wild-type strain NZ131, and its isogenic mutants, SW572 and SW573.................................................................................


87
Fig. 18 Survival ability of wild-type strain and its isogenic mutants in the presence of hydrogen peroxide....................
88
Fig. 19 The principle of yeast two hybrid system............................ 89
Fig. 20 Schematic map of the construction of plasmid pMW414... 90
Fig. 21 Western blot of AH109::pMW414 (hybridization with anti-OppA polyclonal antibody)..........................................
91
Fig. 22 β-galactosidase filter assay of the transformants that may interact with OppA.…………………….............................
92
Fig. 23 Plasmid retransformed into yeast strain AH109.................. 93
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