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系統識別號 U0026-0812200915241353
論文名稱(中文) Srv在A群鏈球菌致病機轉中的角色
論文名稱(英文) The role of Srv in group A streptococcal pathogenesis
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 97
學期 2
出版年 98
研究生(中文) 羅晟展
研究生(英文) Cheng-Chan Lo
電子信箱 t3696405@mail.ncku.edu.tw
學號 t3696405
學位類別 碩士
語文別 中文
論文頁數 89頁
口試委員 口試委員-鄧景浩
口試委員-張晃猷
指導教授-吳俊忠
口試委員-何漣漪
中文關鍵字 致病機轉  SLO 溶血素  A群鏈球菌  熱源性外毒素B 
英文關鍵字 mga  srv  C5a peptidase  emm  scpA  speB  GAS  streptococcal pyrogenic exotoxin B  Streptolysin O  slo  M protein  streptococcus pyogenes 
學科別分類
中文摘要 A群鏈球菌是常見的致病菌,它可以引起很廣泛的人類疾病。目前在A群鏈球菌中已知有許多總體性的調控因子參與致病機轉的調控,如 mga, rgg, covR 等…。然而,在毒力因子的調控網中還存在許多的爭議與未知的調控機制,如 Srv 便是一種 CRP/FNR 家族的轉錄調控因子,參與A群鏈球菌複雜的調控網路。本研究主要針對Srv探討它如何影響下游基因。由北方墨點法、西方墨點法、SpeB 活性試驗或冷光 speB 啟動子活性試驗都證明 Srv 是 speB 的負向調控因子。SpeB 是一種半胱胺酸蛋白水解,在A群鏈球菌感染中扮演重要的毒力因子。然而,先前的研究發現高量表現 SpeB 的 srv 突變株在小鼠感染模式中毒力顯著下降,這表示可能還有其他毒力因子被 Srv 所調控。為了搜尋有哪些毒力因子可能被 Srv 調控,本研究在A群鏈球菌全基因體序列中搜尋預測的 Srv 結合序列,發現在 mga 與 slo 基因的上游有 Srv 的結合序列,而 Mga 已知是一個重要的調控因子,它可以正向調控 M protein (emm) 與 C5a peptidase (scpA)。由 RT-PCR、北方墨點法及real time RT-PCR 顯示在 srv 突變株中 mga、emm、scpA、slo 表現量有部分下降,且在互補株中恢復。冷光 mga 啟動子活性試驗也顯示 srv 突變株中的 mga 活性低於野生株約兩倍。此外,由 real time RT-PCR 與西方墨點法的分析發現 Srv 於 log phase 高量表現,此表現型態與 mga 相符。在 srv 突變株中也發現 SLO 溶血素活性降低,利用人類全血殺菌試驗證實突變株的相對抗殺菌能力也低於野生株約 80%。這些研究結果顯示 Srv 對於A群鏈球菌在血液中的存活扮演很重要的角色,它不僅可以藉由調控 mga 來抵抗殺菌效果,而且也調控 slo 來逃脫吞噬作用。
英文摘要 Group A streptococcus (GAS) is a common pathogen that can cause a wide-spectrum of human diseases. Several global regulators have been extensively studied in GAS such as mga, rgg, covR etc. However, there still have a lot of controversy and unknown mechanisms that are involved in virulence regulation. Srv is a Crp/Fnr family transcriptional regulator and involved in a complex regulatory network of GAS. The aim of this study was to understand how Srv affected the downstream genes. The northern blot, western blot, SpeB activity assay and luciferase speB promoter assay all showed Srv is a negative regulator of speB, Streptococcal pyrogenic exotoxin B, a cysteine proteinase, which plays an important role in GAS infection. However, the highly expressed speB in a srv mutant strain showed low virulence in mice model reported previously, suggesting some other virulence factors may be involved. In order to find out which virulence factors can be regulated by Srv, the putative Srv binding box in GAS whole genome was searched. Two genes, mga and slo had the Srv putative binding box. Mga is an important global regulator, which has shown a regulation of M protein (emm) and C5a peptidase (scpA). RT-PCR, Northern blot and real time RT-PCR showed mga, emm, scpA, and slo decreased expression in srv mutant, and restored in a complementary strain. Luciferase assay also showed that the mga activity in srv mutant was two times lower than that of wild-type strain. In addition, Srv showed a highly expression in log phase by real time RT-PCR and western blot which is correlated with the expression pattern of mga. SLO hemolysin activity decreased in the srv mutant. The human whole blood killing assay was also confirmed that the relative resistant to bactericidal effect was 80% decrease in mutant. Based on these results suggest that Srv plays an important role in blood survival, it not only positively regulate mga to resistant the bactericidal effect but also regulate streptolysin O to evade phagocytosis.
論文目次  目錄
 中文摘要 i
 英文摘要 ii
 誌謝 iii
 目錄 iv
 圖表目錄 vii
 符號與縮寫 viii
 緒論 1
 材料方法 12
I. 實驗藥品、溶液配方及儀器 12
II. 菌種、質體來源 12
III. 實驗菌種培養及其保存 12
IV. DNA 之操作 12
A. 大腸桿菌E. coli 12
A-i. 質體DNA之萃取 12
A-ii. 質體DNA 之選殖13
A-iii. 勝任細胞(Competent cell) 的製備 13
A-iv. 大腸桿菌細胞轉型作用(Transformation) 14
B. A 群鏈球菌 14
B-i. 質體DNA 之萃取 14
B-ii. 染色體DNA 之萃取14
B-iii. A 群鏈球菌電穿孔轉型作用(Electroporation) 15
B-iv. 南方墨漬雜交法(Southern blotting hybridization) 15
B-iv.i. 探針(Probe) 之製作 15
B-iv.ii. 染色體DNA 之限制酶切割16
B-iv.iii. DNA之轉漬(Transfer) 16
B-iv.iv. 雜交反應(Hybridization) 16
B-iv.v. 清洗(Wash) 與呈色作用(Detection) 17
C. 聚合酶連鎖反應 17
D. DNA 電泳位移試驗(EMSA) 17
D-i. DNA Native PAGE 與Target DNA 之製備18
D-ii. DNA 與蛋白質結合緩衝液之條件與電泳 18
D-iii. 染色與呈色照相 18
V. RNA 之操作 19
A. A 群鏈球菌RNA 之抽取19
B. 北方墨點法 (Northern blot hybridization) 19
C. Reverse transcriptase PCR (RT-PCR) 分析20
D. Real-time RT-PCR 20
VI. 蛋白質之操作 21
A. A 群鏈球菌總蛋白質之萃取 21
B. A 群鏈球菌培養液中總蛋白質之萃取 21
C. 蛋白質濃度之測定 22
C-i. Bradford assay 22
C-ii. Lowry assay 23
D. 蛋白質膠體電泳(SDS-PAGE) 23
E. 西方點墨法 (Western Blotting) 23
F. Srv 重組蛋白之純化 24
G. 小鼠 Anti-Srv 多株抗體血清之製備 25
H. 小鼠 Anti-SpeB (C192S)多株抗體之來源25
VII. A 群鏈球菌表現型之分析 25
A. 生長曲線 25
B. 鏈球菌熱源性外毒素B (SpeB)蛋白質水解活性測試 25
C. 鏈球菌溶血素O (SLO) 活性測定 26
D. 冷光酶啟動子活性試驗(Luciferase promoter activity
assay) 26
E. A 群鏈球菌抗全血殺菌能力試驗 27
VIII. 生物資訊分析之工具 27
A. 全基因體調控子分析工具 - Virtual Footprint version 3.0
27
B. 蛋白質結構分析工具– PHYRE version 0.2 28
C. 統計學分析 28
 結果
I. 構築 srv 突變株、互補株、空載體對照株 29
A. 利用雙置換同源重組法來構築 srv 突變株 29
B. 構築互補株及空載體對照株 30
II. 突變株與互補株並不影響其生長活性 30
III. 調控因子Srv 負向調控speB 31
A. srv 突變株增加speB 的mRNA 與蛋白質表現量,且SpeB 活性增
加31
B. 空載體不影響野生株 SpeB 活性,但造成srv 突變株SpeB 表現
量下降32
C. srv 突變株中speB 啟動子活性增加32
IV. mga、slo 啟動子區域含有Srv 辨識之DNA 結合位點33
V. 調控因子 Srv 正向調控mga、emm、scpA、slo 33
A. srv 突變株降低mga、emm、scpA、slo 之mRNA 表現量33
B. srv 突變株中mga 啟動子活性降低 34
VI. 純化 Srv 重組蛋白並製備小鼠Anti-Srv 多株抗體血清35
VII. Srv 於log-phase 高量表現 36
VIII.rSrv 具DNA 結合能力可減緩A 群鏈球菌DNA 片段之泳動 36
IX. srv 突變株降低SLO 溶血素活性37
X. srv 突變株顯著降低抗全血殺菌能力 38
 討論 39
 參考文獻 47
 圖表 60
 附錄 80
I. 補充圖表 80
II. 藥品與廠商 83
III. 溶液配方 85
 自述 89
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