臺灣博碩士論文加值系統

Proteus mirabilis(奇異變形桿菌)屬於腸桿菌科，革蘭氏陰性的兼性厭氧菌，在健康人腸道內為正常菌叢，但在腸道以外的地方則會造成伺機性的感染。最常見的即為泌尿道感染(UTI)，為院內感染的常見菌。P. mirabilis的特徵是當其處於固體表面時，會從單一細胞的vegetative cells變化成多細胞、多鞭毛具有表面移行能力的swarmer cells，由文獻已知P. mirabilis表面移行的能力與其他致病因子有關，例如溶血酶以及尿素酶活性等。
此一菌株早在1972年即被發現對polymyxin B (PB)具有很強的抗藥性，目前已知是因為其LPS(lipopolysaccharide)的lipid A上面的磷酸根被aminoarabinose所修飾，使得外膜的負電荷被中和，而PB就無法利用其正電荷和細菌外膜結合而失去殺菌能力。
在其他革蘭氏陰性菌，如：Escherichia coli、Salmonella Typhimurium等，PB的感受性與LPS的修飾作用有關，而這些修飾作用可藉由雙組成系統所調控。其中Salmonella Typhimurium LPS分子的修飾同時受PhoP/PhoQ、PmrA/PmrB、RcsC/YojN/RcsB三種system所調控。
我論文的目的是想看在P. mirabilis中是否也存在著雙組成調控系統和PB的感受性有關。由於PB的感受性和swarming都和雙組成調控系統及菌體envelope構造有關，故同時觀察這些雙組成調控系統和swarming及其他致病因子間的關係。首先我們在已發表的P. mirabilis基因體中尋找和Salmonella PhoP/PhoQ相似的蛋白質及基因序列，再將實驗室菌株P. mirabilis P19的目標基因定序出來，一方面以生物資訊學做分析，一方面挑選突變菌株以作進一步的研究。目前找到的兩個雙組成調控系統，其中一個(RppA/RppB, Regulator of Polymyxin B susceptibility in Proteus)和PB的抗藥性有關，突變菌株的感受性較野生菌株上升大於1000倍。我們也發現到當PB不存在時，rppA基因的突變會造成表面移行、LPS pattern、鞭毛蛋白以及溶血酶活性的改變。此外，當PB不存在時，野生菌株及rppA突變株的外膜組成幾乎相同；而當PB存在時，野生菌株可感知此訊息而產生一新的蛋白質。不同於外膜的變化，rppA突變株的LPS不管在有無PB存在時皆和野生菌株不相同，此外也發現PB可以刺激野生菌株的LPS產生更多的變化，而rppA突變株中則沒有此種情形。因此推測這些改變可能皆與PB的抗藥性有關，而RppA/RppB系統的調控參與在其中。我們也觀察到在PB的刺激下，野生菌株的許多致病因子(表面移行、溶血酶、生物膜生成等)會受影響而產生不同於rppA突變株的變化，推測PB可能為此雙組成調控系統的訊息因子之ㄧ。P. mirabilis中有雙組成系統可調控其對PB的感受性、表面移行及致病因子的現象是在本實驗室首次發現。而用Real-Time PCR的方法也發現在PB以及低鎂離子的環境中，rppA基因的表現量有上升，這和過去Salmonella的PhoP/PhoQ系統有正向自我調控的現象相符合。而另一雙組成調控系統(RhpA/RhpB, Regulator of haemolysin in Proteus)和PB的關係不明顯，主要可能和溶血酶以及入侵細胞能力的調控有關係。

Proteus mirabilis is a facultative Gram-negative bacterium and a member of the family Enterobacteriaceae. It is an opportunistic pathogen frequently causes urinary tract infection (UTI) in hospital patients. One of the characteristics of P. mirabilis is its dramatic morphological change on solid surface. When growing on solid surface, it changes from single rod-shaped swimmer cell to an elongated multicellular swarmer cell and it can swarm on agar plate resulting in a bulled-eye pattern. P. mirabilis produces many virulence factors such as haemolysin and urease whose production is co-ordinated with swarmer cell differention.
P. mirabilis is naturally resistant to PB, which is a kind of cationic antimicrobial peptides. It is known that the modification of the lipid A of P. mirabilis by aminoarabinose results in PB resistance. In E. coli and Salmonella Typhimurium, LPS modification regulated by two-component system causes the change of PB susceptibility. We reported here that there is a two-component system (we call RppA/RppB, Regulator of Polymyxin B susceptibility in Proteus) which is associated with PB resistance, swarming and virulence in P. mirabilis. The PB susceptibility elevates more than 1,000 folds in rppA mutant than in wild-type. In the absence of PB, we observed rppA mutation results in the change of haemolysin activity, swarming, LPS pattern and flagellin production.We demonstrated PB caused significant change in LPS and OMP profiles in wild-type but not in the mutant. This imply that both LPS and OMP change modulated by RppA pathway involve in the resistance of PB in P. mirabilis. Furthermore, we find that PB has effect on haemolysin activity and biofilm production through the RppA/RppB pathway. To our knowledge, this is the first finding that a two-component system regulates PB resisitance, swarming and virulence in P. mirabilis.
In addition to RppA/RppB, we also found another two-component system that has high identidy to Salmonella PhoP/PhoQ in P. mirabilis. The system has no obvious relationship with polymyxin B susceptibility but play a role in the production of haemolysin and ability of invasion.

口試委員審定書
誌謝…………………………………………………………………………………一
目錄……………………………………………………………………………… 二
表目錄…………………………………………………………………………… 四
圖目錄…………………………………………………………………………… 五
附錄目錄………………………………………………………………………… 七
中文摘要…………………………………………………………………1
英文摘要…………………………………………………………………3
第一章 緒論………………………………………………………………………5
第一節 奇異變形桿菌(Proteus mirabilis)介紹…………………………5
第二節 多黏菌素B(polymyxin B)相關介紹…………………………11
第三節 研究動機與目的………………………………………………16
第四節 實驗設計………………………………………………………17
第二章 研究方法與材料……………………………………………………… 19
第一節 實驗材料………………………………………………………19
第二節 實驗方法………………………………………………………24
(一) 尋找P. mirabilis中與S. Typhimurium PhoP/PhoQ相似的蛋白質及其基因片段………………………………………24
(二) 基因剔除突變菌株之建構………………………………28
(三) 對polymyxin B感受性及致病因子測定……………………34
(四) 雙組成調控系統之基因體研究…………………………41
第三章 實驗結果……………………………………………………………… 43
第一節 尋找與Salmonella PhoP/PhoQ相似的蛋白質及基因片段……43
第二節 基因剔除突變菌株之建構……………………………………45
第三節 雙組成調控系統與polymyxin B感受性及細菌致病因子的關係
…………………………………………………………………47
(一) RppA/RppB系統：rppA基因剔除突變株……………………………………………47
(二) RhpA/RhpB系統：rhpA基因剔除突變株…………………………………………… 53
第四章 結論與討論……………………………………………………………… 55
第一節 RppA/RppB雙組成調控系統………………………………… 55
第二節 RhpA/RhpB雙組成調控系統……………………………………60
第五章 表…………………………………………………………………………61
第六章 圖…………………………………………………………………………65
第七章 附錄………………………………………………………………………94
第八章 參考文獻…………………………………………………………………103

表目錄
表一、實驗中所使用的菌株及質體………………………………………………61
表二、實驗中所使用的引子………………………………………………………62
表三、P. mirabilis P19、△rppA、rppA complement以及△rhpA菌株對PB的MIC值………………………………………………………………………………64
表四、P. mirabilis P19、dA10在PB存在與否時的EPS量…………………… 64
圖目錄
圖一、引子位置示意圖……………………………………………………………65
圖二、RppA/RppB核醣核酸序列及胺基酸序列…………………………………66
圖三、RhpA/RhpB核醣核酸序列及胺基酸序列…………………………………67
圖四、RppA/RppB的mutiple alignment…………………………………………68
圖五、RhpA/RhpB的mutiple alignment………………………………………… 69
圖六、RppB的穿膜功能區預測…………………………………………… 70
圖七、RppA/RppB之3D立體結構圖……………………………………………71
圖八、LA in vitro PCR示意圖……………………………………………………72
圖九、將rppA基因剔除之質體建構示意圖……………………………………73
圖十、將rhpA基因剔除之質體建構示意圖……………………………………74
圖十一、南方點末法確定rppA基因剔除的突變株……………………………75
圖十二、南方點末法確定rhpA基因剔除的突變株……………………………76
圖十三、P. mirabilis P19及△rppA在PB存在與否時的生長曲線圖…………77
圖十四、P. mirabilis P19及△rppA對PB的存活率比較………………………77
圖十五、P. mirabilis P19及△rppA在PB存在與否時，外膜蛋白的差異性…78
圖十六、P. mirabilis P19及△rppA在PB存在與否時，脂多醣的差異性……79
圖十七、A. P. mirabilis P19及△rppA的爬行距離比較
B. P. mirabilis P19及△rppA在PB存在與否時，爬行距離比較……80
圖十八、A. P. mirabilis P19及△rppA的爬行速度比較
B. P. mirabilis P19及△rppA在PB存在與否時，爬行速度比較……80
圖十九、P. mirabilis P19及△rppA在含不同濃度PB的培養基上的爬行比較
………………………………………………………………………… 81
圖二十、P. mirabilis P19及△rppA在PB存在與否時，鞭毛蛋白量的差異性
頁次
………………………………………………………………………… 82
圖二十一、P. mirabilis P19及△rppA在PB存在與否時，溶血酶活性的比較
……………………………………………………………………… 83
圖二十二、P. mirabilis P19及△rppA的溶血酶基因表現比較…………………83
圖二十三、A. P. mirabilis P19及△rppA在PB存在與否時，細胞入侵率的比較
B. P. mirabilis P19及△rppA在PB存在與否時，對Tween 20的存活率比較……………………………………………………………… 84
圖二十四、NTUB1分別被P. mirabilis P19及△rppA感染後的細胞型態……85
圖二十五、P. mirabilis P19及△rppA的尿素酶活性比較………………………87
圖二十六、P. mirabilis P19及△rppA在PB存在與否時，生物膜產量的比較
…………………………………………………………………………87
圖二十七、PB刺激下，rppA基因表現情形…………………………………… 88
圖二十八、低鎂離子刺激下，rppA基因表現情形…………………………… 88
圖二十九、P. mirabilis P19及△phoP的生長曲線圖…………………………… 89
圖三十、P. mirabilis P19及△phoP的爬行距離比較……………………… 89
圖三十一、P. mirabilis P19及△phoP的爬行速度比較……………………… 90
圖三十二、P. mirabilis P19及△phoP的溶血酶活性比較…………………… 91
圖三十三、P. mirabilis P19及△phoP的溶血酶基因表現比較……………… 91
圖三十四、P. mirabilis P19及△phoP的細胞入侵率比較…………………… 92
圖三十五、NTUB1分別被P. mirabilis P19及△phoP感染後的細胞型態… 93

附錄目錄
附錄一、P. mirabilis的致病因子及表現部位…………………………………94
(Microbiology and Molecular Biology Reviews, 61, 65–89;
Microbes and Infection, 2, 1497−1505)
附錄二、P. mirabilis的swarming cycle……………………………………95
(Microbiology and Molecular Biology Reviews, 61, 65–89)
附錄三、P. mirabilis LPS的lipid A上的磷酸根被4-aminoarabinose所修飾) …96
(Microbiology and Molecular Biology Reviews, 61, 65–89)
附錄四、革蘭氏陰性菌的細胞膜結構……………………………………………96
(Annu Rev. Biochem., 71, 635-700)
附錄五、Polymyxin B的結構……………………………………………………97
附錄六、Salmonella Typhimurium受雙組成調控系統PhoP/PhoQ, PmrA/PmrB, RcsC/YojN/RcsB所調控……………………………………………… 98
(Journal of Bacteriology, 183, 1835–1842.2001 Mar;
Molecular Microbiology, 47, 335–344)
附錄七、Salmonella Typhimurium的PhoP/PhoQ的功能區……………………99
附錄八、pGEM®-T Easy cloning vector map (Promega) ………………………100
附錄九、pUT-Tn5 (mini-Tn5) map……………………………………………… 101
附錄十、pACYC184 map……………………………………………………….102

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