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系統識別號 U0026-2208201113481800
論文名稱(中文) A群鏈球菌perR基因對DNase之調控
論文名稱(英文) Regulation of DNase by the perR gene of 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 99
學期 2
出版年 100
研究生(中文) 郭欣慈
研究生(英文) Hsin-Tzu Kuo
學號 T36981011
學位類別 碩士
語文別 中文
論文頁數 79頁
口試委員 指導教授-吳俊忠
口試委員-何漣漪
口試委員-蔡佩珍
口試委員-鄧景浩
口試委員-廖寶琦
中文關鍵字 A群鏈球菌 
英文關鍵字 group A streptococcus  PerR  DNase 
學科別分類
中文摘要 化膿性鏈球菌(Streptococcus pyogenes)又稱作A群鏈球菌(group A streptococcus,簡稱GAS)為感染人類之致病菌,造成輕微的表皮感染到嚴重深層組織的侵入性疾病。PerR (peroxide stress response regulator) 為GAS之調控因子,已知和GAS適應氧化壓力反應及鐵的平衡有關,而perR突變株對於抵抗多形核白血球的清除能力比野生株低。利用二維電泳分析,發現perR突變株與野生株有19個分泌型蛋白質表現具有顯著的差異。其中一蛋白質為mitogenic factor 3 (Mf3),為已知的DNase。本研究主要探討PerR對於Mf3及其他DNase的調控以及此調控在GAS致病機轉中的角色。為了瞭解mf3的毒力,我們進一步構築mf3的突變株,發現其在人類全血中的存活能力較低,且在小鼠感染中的毒力也會下降。mf3的表現和生長曲線呈正相關,但perR突變株mf3的表現量會多於野生株。進一步分析PerR對GAS三個DNase基因(sda1,spd及mf3)的調控。在一般培養液培養下,sda1的表現量在perR突變株及野生株並沒有差異,但spd在培養8小時時,perR突變株的表現量增加。在硫酸亞鐵的刺激下,PerR並不會對三個DNase基因的表現造成影響。但在過氧化氫的刺激下,野生株的sda1會被誘發,且隨劑量的增加而有遞增的表現,而perR突變株中表現量卻降低。反之,在過氧化氫的刺激下,mf3及spd在野生株中則會隨著劑量增加而表現下降。此結果顯示在氧化壓力下PerR 為sda1表現必需的調控因子。在已知的三個DNase基因中,sda1具有較強DNA 分解能力以及和GAS致病力最為相關。Sda1已被報導可分解neutrophil extracellular traps (NETs)上的DNA以逃脫免疫攻擊。將GAS和多核型白血球培養後,發現野生株感染後NETs的數目比突變株少,推測為在氧化壓力下,野生株sda1被誘發表現而增加分解NETs的能力。這些結果指出PerR為一個雙功能性的調控因子,在不同環境刺激下影響DNase基因的表現進而影響其功能,這在GAS的致病機轉中扮演一個重要的角色。
英文摘要 Streptococcus pyogenes (group Astreptococcus, GAS) is a bacterial pathogen restricted to human, and causes diseases ranging from superficial to deep tissue infection. In order to defend oxidative stress produced from immune cells, the regulator PerR (peroxide stress response regulator)is known to playa role in the adaptive response. PerR is also involved in regulation of iron hemostasis and is necessary for virulence of GAS. Our results showed that the perR mutant decreased resistance to PMN killing. In addition, 2-D electrophoresis analysis showed19 spots were either up regulated or down regulated expression in the perR mutant. Among them, a DNase (mitogenic factor 3, MF3) was identified and mutant was also constructed.The aimsof my project were to understand the roles of PerR in regulation of Mf3 and other DNases of GAS, and the effects of this regulation network to GAS pathogenesis. The mf3 mutant showed the decrease survival rate than the wild-typein human whole blood bactericidal assayand the attenuated virulence in mice infection. RT-PCR and real-time PCR showed increased mf3 expression in theperR mutant. Electrophoretic mobility shift assays showed PerR directly binds to Per boxes in the mf3 promoter region. In order to understand how PerR regulated DNase activity, three DNases genes (sda1,spd, and mf3) were further analyzed in wild-type and perR mutant strains under different conditions including ferrous ion and hydrogen peroxide treatment. The results showed no effect on sda1,spd, and mf3 expressionin wild-type strain under the ferrous ion treatments, while spd and mf3 expression were increased in the mutant. sda1expression was increased in wild-type strain, while mf3 and spd expressionswere decreased after hydrogen peroxide treatments.These results indicated that sda1 expression under oxidative stress is PerR-dependent. Sda1 has been found it degraded DNA of neutrophil extracellular traps (NETs) and allowed GAS to escape from phagocytes killing. In fluorescence images of NETs, less NETs were presented in wild-type thanperR mutant supporting that sda1 was only induced in wild-type strain to degrade the NET structure. In conclusion, PerR acts as a bifunctional regulator to regulate DNase gene in different environmental conditions which may play an important role in the GAS pathogenesis.
論文目次 中文摘要 i

英文摘要 ii

誌謝 iv

目錄 v

圖表目錄 ix

符號及縮寫 x

緒論 1
一、A群鏈球菌簡介 1
二、A群鏈球菌造成之疾病 1
三、A群鏈球菌之流行病學調查 2
四、A群鏈球菌之毒力因子 3
A.抵禦抗微生物肽 (Antimicrobial peptides, AMP) 4
B.干擾補體(Complement)功能 4
C. 抑制細胞免疫屏障 (Cell barrier) 5
C-1. 防止吞噬細胞 (Phagocytes)聚集 5
C-2. 對抗吞噬細胞 (Phagocytes)內毒殺作用 6
C-3. 產生殺白血球毒素 (Leukocidal toxins) 6
C-4. 細菌多醣夾膜 (Polysaccharide capsules)之防禦作用 7
D. 逃脫免疫細胞extracellular traps (ETs)之攻擊 7
D-1. 分解extracellular traps (ETs) 7
D-2. 抵禦ETs上之抗菌物質及抑制 ETs生成 8
五、A群鏈球菌與氧化壓力 8
六、Peroxide response regulator (PerR) 之介紹 9
七、A群鏈球菌之DNases 10
八、研究目的 11
材料與方法 12
一、菌種、質體及動物來源 12
二、實驗藥品及溶液配方 12
三、實驗菌種培養及保存 12
四、DNA 實驗操作 12
A.大腸桿菌 (E. coli) 12
A-1. 質體DNA 萃取 12
A-2. 限制酶酵素切割及DNA接合反應 13
A-3. 製備勝任細胞 (Competent cell ) 13
A-4. 大腸桿菌轉形作用 (Transformation) 13
B. A群鏈球菌 (Group A streptococcus) 14
B-1. 質體DNA 萃取 14
B-2. 染色體DNA 萃取 14
B-3. A群鏈球菌電穿孔轉型作用 (Electroporation) 15
B-4. 南方墨點雜交法 (Southern blotting hybridization) 15
B-4-1. 製備探針 (probe) 15
B-4-2. 染色體DNA之限制酶切割反應 (Restriction enzyme digestion) 15
B-4-3. DNA電泳與轉漬 (Transfering) 16
B-4-4. 雜交反應 (Hybridization) 16
B-4-5. 清洗 (Wash) 與呈色作用 (Detection) 16
C. 聚合酶連鎖反應 (Polymerase chain reaction, PCR) 17
D. DNA 電泳位移實驗 (Electrophoretic mobility shift assay, EMSA) 17
五、RNA 實驗操作
A. A群鏈球菌RNA 萃取 17
A. A群鏈球菌RNA萃取 17
B.北方墨點法 (Northern blot hybridization) 18
C. Reverse transcriptase PCR (RT-PCR) 分析 19
D. Real-time RT-PCR 分析 19
六、蛋白質實驗操作 20
A. A群鏈球菌總蛋白質萃取
20
B. A群鏈球菌培養液中總蛋白萃取
20
C.蛋白質濃度之定量
21
C-1. Bradford assay
21
C-2.Lowry assay
21
D.蛋白質膠體電泳 (SDS-PAGE)
21
E.西方點墨法 (Western blotting)
22
F. Mf3重組蛋白之純化
22
F-1. 重組蛋白質之誘導 (Induction)
22
F-2. 重組蛋白質之純化 (Purification)
23
G.小鼠 Anti-Mf3 多株抗體置備
23
H. Mf3 重組蛋白功能分析
24
H-1. rMf3 之DNase活性測定 24
H-2. rMf3 之superantigen特性測定
24
I. SpeA重組蛋白來源
25
七、 A群鏈球菌表現型之分析
25
A. A群鏈球菌之生長曲線
25
B. A群鏈球菌抗全血殺菌能力試驗
25
C. A群鏈球菌之小鼠感染模式 25
D. A群鏈球菌抗PMN (Polymorphonuclear) Leukocyte能力試驗 25
D-1. PMN leukocyte之分離 26
D-2.抗PMN leukocyte 能力試驗
26
E. A群鏈球菌清除Neutrophil extracellular trap (NET)能力試驗
27
八.生物資訊分析之工具
27
A. 細菌啟動子分析工具- BPROM 27
B.Signal Peptide 預測工具- SignalP 3.0 Server
27
C.統計學分析
28
結果
29
一、perR突變降低抗多核性細胞清除的能力
29
二、構築mf3突變株及互補株
29
A.利用雙置換同源性重組構築mf3突變株
29
B.構築mf3互補株
30
三、突變株與互補株並不影響其生長活性
31
四、mf3基因突變減弱A群鏈球菌的毒性
31
五、純化Mf3重組蛋白並置備小鼠Anti-Mf3 多株抗體血清
32
六、r-Mf3在二價離子存在下具有DNase的功能
32
七、測定r-Mf3之超級抗原(Superantigen)的特性
33
八、調控因子PerR調控mf3之機制
33
A. perR突變株增加mf3的mRNA表現量 33
B.PerR重組蛋白可結合mf3基因的promoter上
34
九、調控因子PerR不調控sda1但在stationary phase負向調控spd
34
十、二價鐵的加入不影響DNase基因表現
35
十一、三價鐵的加入降低mf3及sda1 mRNA的表現
35
十二、在氧化壓力下sda1 mRNA的誘導會受到PerR正向調控
35
十三、PerR對DNase調控在NETs (Neutrophil extracellular traps)清除中扮演角
色 36
討論
37
一、Mf3 在A群鏈球菌中的角色
37
A. Mf3在A群鏈球菌致病機轉中所扮演的角色
37
B. Mf3分解DNA的能力
37
C. Mf3並不具有超級抗原的特性
38
二、PerR 負向調控mf3mRNA的機制
38
三、PerR在不同環境下調控DNase基因之表現
40
A.二價鐵 (Ferrous iron, Fe2+)與三價鐵 (Ferric iron, Fe3+)
40
B.氧化壓力
41
四、PerR 對DNase的調控在A群鏈球菌致病機轉中所扮演的角色
42
五、A群鏈球菌新穎DNase-SpnA
43
六、總結
44
參考文獻
45
圖表
54
附錄 73
I藥品與廠商
73
II溶液配方
75
自述 79


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