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系統識別號 U0026-2608201317545800
論文名稱(中文) A群鏈球菌在血管內皮細胞內存活能力的探討
論文名稱(英文) Intracellular survival of group A streptococcus in endothelial cell
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 101
學期 2
出版年 102
研究生(中文) 陳皓玟
研究生(英文) Hao-Wen Chen
學號 T16001011
學位類別 碩士
語文別 中文
論文頁數 83頁
口試委員 指導教授-吳俊忠
召集委員-何漣漪
口試委員-鄧景浩
口試委員-江倪全
中文關鍵字 A群鏈球菌  血管內皮細胞  酸鹼值 
英文關鍵字 group A streptococcus  endothelial cell  pH value 
學科別分類
中文摘要   化膿性鏈球菌 (Streptococcus pyogenes) 亦稱為A群鏈球菌 (group A streptococcus, GAS) 為重要的人類致病菌,可廣泛造成多種人類疾病。過去A群鏈球菌被視為胞外致病菌,但近年來越來越多的研究指出,A群鏈球菌能夠於不同的細胞中存活並繁殖;我們的研究團隊發現,部分會引起侵入性疾病的菌株具有在人類微血管內皮細胞株 (human microvascular endothelial cell line-1,HMEC-1) 中存活的能力,而細菌在細胞中的存活能力可能與其造成侵襲性疾病有關,但目前對於A群鏈球菌在細胞內存活之機轉仍不清楚。環境中酸鹼值的變化會影響基因的表現,其於A群鏈球菌的致病機轉上扮演著重要的角色,因此本研究探討環境中酸鹼值的變化是否與 NZ131 在內皮細胞中的存活能力有關。我們分別以酸性及中性培養液處理A群鏈球菌後感染內皮細胞,相較於中性培養液處理後的A群鏈球菌,受到酸性培養液處理的A群鏈球菌在內皮細胞中存活的能力較差;螢光顯微鏡下,我們觀察到中性培養液處理之A群鏈球菌在內皮細胞中有繁殖的情形,而酸性處理之A群鏈球菌則受到宿主細胞溶酶體的環繞及清除。以 bafilomycin A1 抑制宿主細胞溶酶體的功能後,酸性處理之A群鏈球菌能在宿主細胞內繁殖,證明酸性培養液處理之A群鏈球菌仍具有在內皮細胞中存活的能力。以 real-time RT-PCR 分析, sagB、slo 及 spn 等毒力基因於中性環境處理下具有較高的表現量,而 speB 則於酸性環境下具有較高的基因表現量。NZ131 sagB 突變株於中性及酸性環境處理後,皆無法於內皮細胞中存活,但當 NZ131 失去 SpeB 之活性,則不影響其於細胞內之存活能力。這些結果指出,酸鹼值所造成的基因表現差異會影響A群鏈球菌在內皮細胞中的存活能力,並且在中性環境下表現量高的基因似乎較有可能參與A群鏈球菌在內皮細胞中的存活。
英文摘要   Streptococcus pyogenes (group A streptococcus, GAS) is an important human pathogen that causes wide-spectrum human diseases. GAS has been considered as the extracellular pathogen, but several studies showed that GAS could survive and multiply inside of different types of cells. Our research team that invasive GAS strains are able to multiply in human microvascular endothelial cell line-1 (HMEC-1), suggesting that survival inside of the endothelial cells may play an important role for invasive diseases caused by GAS. However, the mechanisms of intracellular GAS survival are still unknown. Since environmental pH affects gene expression that plays a central role on GAS pathogenesis, we investigated the role of environmental pH in NZ131 survival in HMEC-1. GAS were pretreated with acidic or neutral culture medium before incubating with endothelial cells. When compared to neutral medium treatments, NZ131 with acidic medium pretreatment showed lower survival ability in HMEC-1. Using the fluorescence microscopy, we found that neutral medium pretreatment GAS could multiply in the HMEC-1, but acidic medium pretreatment GAS would be surrounded and degraded by lysosome. After treating of lysosome inhibitor, bafilomycin A1, acidic medium pretreatment GAS recovered the survival ability. These results demonstrate that acidic medium pretreatment GAS could survive inside of the endothelial cells. By real-time RT-PCR analysis, expressions of sagB, slo and spn in acidic medium pretreatment were lower than in neutral, and speB in acidic medium pretreatment was higher than in neutral. Furthermore, NZ131 sagB mutant lose the survival activity after acidic and neutral environmental pretreatment. NZ131 without SpeB activity did not affect GAS survival activity in HMEC-1. Overall, the difference of gene expression caused by pH influence the survival activity of GAS in HMEC-1. The higher-expression genes of GAS where is under the neutral conditions may participate in survival inside of the endothelial cells.
論文目次 中文摘要i
英文摘要ii
誌謝iv
目錄v
表目錄ix
圖目錄x
符號及縮寫xi
緒論1
一、A群鏈球菌1
I.簡介1
II.疾病與流行病學調查1
III.已知毒力因子3
A.鏈球菌溶血素O (Streptolysin O, SLO)4
B.鏈球菌溶血素S (Streptolysin S, SLS)5
C.Nicotine-Adenine-Dinucleotidase (NAD-glycohydrolase, NADase)6
D.M 及 M-like 蛋白質8
二、A群鏈球菌逃避宿主細胞清除及生存於宿主細胞內的機制9
三、宿主細胞清除A群鏈球菌的機制10
A.Macroautophagy:10
B.Microautophagy:10
C.Chaperone-mediated autophagy (CMA):10
四、研究目的11
材料與方法13
一、菌種及質體來源13
二、實驗藥品及藥劑配方13
三、實驗菌種培養及保存13
四、細菌 DNA 之萃取13
I.大腸桿菌 (E. coli)13
A.質體DNA之萃取14
B.聚合酶連鎖反應 (Polymerase chain reaction, PCR)14
C.限制酶酵素切割及DNA接合反應15
D.勝任細胞 (Competent cell) 的製備15
E.大腸桿菌細胞轉型作用 (Transformation)15
II.A群鏈球菌 (Group A streptococcus)16
A.染色體 DNA之萃取16
B.A群鏈球菌電穿孔轉型作用 (Electroporation)16
五、南方墨點雜交法 (Southern blotting hybridization)17
I.探針 (Probe) 之製備17
II.染色體DNA之限制酶切割17
III.Genomic DNA之電泳與轉漬 (Transfering)17
IV.雜交反應 (Hybridization)18
V.清洗 (Wash) 與呈色作用 (Detection)18
六、A群鏈球菌RNA之萃取19
七、Reverse transcriptase PCR (RT-PCR) 分析20
八、Real-time RT-PCR20
九、蛋白質酶活性測試21
十、人類微血管內皮細胞株 (Human microvascular endothelial cell line-1, HMEC-1) 之培養21
I.細胞培養21
II.細胞保存22
III.細胞解凍22
十一、不同酸鹼值培養液處理之A群鏈球菌存活率分析23
I.酸性培養液之配製23
II.存活率分析23
十二、不同酸鹼值培養液處理後之A群鏈球菌於中性環境的生長曲線23
十三、菌株在內皮細胞內存活能力之分析24
I.Gentamicin protection assay24
II.螢光顯微鏡操作25
十四、乳酸脫氫酶 (LDH cytotoxicity assay) 活性測定26
十五、生物資訊分析之工具26
I.比較胺基酸序列之工具26
II.統計學分析27
結果28
一、不同酸鹼值培養液處理後的 NZ131 在內皮細胞中的存活能力不同28
二、於感染初期不同酸鹼值培養液處理後的NZ131對細胞的毒性相同29
三、以螢光顯微鏡觀察受不同處理條件之 NZ131 感染的細胞30
四、中性培養液處理後的NZ131在內皮細胞中的存活情況30
五、酸性培養液處理後的 NZ131 在內皮細胞中的存活情況31
六、不同酸鹼值培養液處理後的 NZ131 於內皮細胞中受清除之狀況31
I.酸性培養液處理後的 NZ131 在內皮細胞中受到溶酶體的清除31
II.中性培養液處理後的 NZ131 在內皮細胞中未受到溶酶體的清除32
七、酸性培養液處理後之 NZ131 可存活於溶酶體失去功能之內皮細胞中33
八、不同酸鹼值培養液處理後的A20在內皮細胞中的存活能力不同33
九、A群鏈球菌在不同酸鹼值培養液之處理下,部分基因表現量有顯著差異34
十、NZ131 sagB突變株不具有在內皮細胞中存活之能力35
十一、NZ131 speB 突變株具有在內皮細胞中存活之能力35
十二、不同酸鹼值刺激後的菌株在中性環境下的生長狀況無顯著差異36
討論37
一、酸鹼值可做為影響A群鏈球菌在內皮細胞中存活能力的調控因子37
A.酸性培養環境對菌體的影響37
B.受感染細胞的受損情況38
二、不同酸鹼值培養液刺激後的A群鏈球菌重新適應中性環境的能力相同38
三、受中性培養液處理之 NZ131 所感染的內皮細胞中包含不同細菌族群39
四、酸性培養液處理之 NZ131 在內皮細胞中無法存活的可能原因39
五、受酸鹼值調控之基因對A群鏈球菌在內皮細胞中存活能力的影響41
六、NZ131 slo 及 nga 突變株之構築44
A.NZ131 slo 突變株之構築44
B.NZ131 nga 突變株之構築45
七、酸鹼值對A群鏈球菌感染內皮細胞能力的調控於致病機轉中所扮演的角色46
八、總結46
參考文獻48
圖表56
附錄72
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