臺灣博碩士論文加值系統

附著寄主細胞，是細菌達成感染的第一步驟。已知，第三型纖毛的表現與克雷白氏肺炎桿菌感染寄主細胞的部位密切相關。本論文主題在探討第三型纖毛的表現與克雷白氏肺炎菌致病過程的關聯：首先，我們以PCR-RFLP的技術分析第三型纖毛黏附蛋白基因型，結果在十七株腦膜炎菌株中發現四種新的黏附蛋白基因型，分別命名為mrkDV1，mrkDV2， mrkDV3和mrkDV4。接著，我們以大腸桿菌JM109為表現載體構築了表現第三型纖毛的重組質體，分別帶有mrkDV1，mrkDV2，mrkDV3和mrkDV4基因型。而藉穿透式電子顯微鏡來觀察這些重組大腸桿菌表現的纖毛，我們發現mrkD基因型的變異會影響第三型纖毛的長度和型態。同時，測試這些重組細菌黏附第四型和第五型膠原蛋白的能力、生物膜的形成與黏附細胞的活性，結果顯示，E. coli JM109[pMrkABCDV3F]在這些測試中，活性皆高於帶有其他三種黏附蛋白基因型的大腸桿菌。我們也發現MrkDv3黏附蛋白上的RGD序列可以決定E. coli JM109[pMrkABCDV3F]黏附HCT-8細胞的專一性。其次，我們也探討第三型纖毛在克雷白氏肺炎桿菌CG43中的表現調控：核酸序列分析顯示第一型纖毛和第三型纖毛的基因群相連。在LB或GCAA培養液中，都可以偵測到第三型纖毛的表現；相反的，只有在mrkA缺損或是fimB大量表現的情況下，才能偵測到第一型纖毛的表現。而在fimB大量表現時，第三型纖毛的表現會明顯下降，這樣的結果暗示著這兩種纖毛的表現有互相調控的關係。而在第一型纖毛和第三型纖毛基因群之間，我們發現有兩個基因和Erwinia chrysathemi調控毒性因子的pecS和pecM相似，分別命名為phgS和phgM。在測量啟動子活性時，我們發現PS-mrkA的活性在phgS或phgM缺損株中，都明顯降低，這暗示著PhgS/PhgM可以調控第三型纖毛的表現。同時，以電泳膠遲滯實驗證明重組蛋白PhgS可以結合PS-mrkA也顯示PhgS具有轉錄調控的功能。另外，我們還找到一段不受PhgS/PhgM影響的啟動子PL-mrkA，顯示第三型纖毛的表現調控可能並不單純。

As generally known, attachment of pathogens to their host is a prerequisite step of infection. The study reports the involvement of type 3 fimbriae, which has been shown as the primary adhesion factor in Klebsiella pneumoniae, in the bacterial pathogenesis. Firstly, four novel mrkD alleles namely mrkDV1, mrkDV2, mrkDV3 and mrkDV4, were identified in seventeen K. pneumoniae meningitis strains. A type 3 fimbriae display system in Escherichia coli was subsequently constructed to determine the effect of MrkD allelic variation on the fimbrial activity. The TEM analysis indicated that the proper growth of the filament and fimbrial morphology were MrkD adhesin dependent. The assessments via measurements of collagen IV and V binding activity, biofilm formation, and cell adherence revealed that the E. coli JM109[pmrkABCDV3F] had the highest level of fimbriae activity and the adhesion to HCT-8 cells is probably through the interaction of the RGD sequence on MrkDv3 with integrin. Secondly, regulation of expression of type 3 fimbriae in K. pneumoniae CG43 is investigated. Sequence analysis revealed that type 1- and type 3-fimbriae gene clusters are physically linked in the genome of K. pneumoniae CG43. The expression of type 3 fimbriae in LB or GCAA medium could be readily demonstrated in the bacteria. In contrast, the expression of type 1 fimbriae was evident only in the mrkA deletion mutant or in the fimB overexpression mutant. Whereas, the overexpression of fimB diminished the expression of type 3 fimbirae suggesting a cross regulation is present for the expression of the two fimbriae. In-between the two gene clusters, homologues of Erwinia chrysanthemi virulence regulatory genes pecS and pecM were identified and named phgS and phgM respectively. The promoter activity measurement revealed that the deletion of phgS or phgM reduced the activity of the putative promoter PS-mrk, which suggesting a PhgS/PhgM-dependent expression of type 3 fimbriae. The binding of the recombinant PhgS to PS-mrk demonstrated by EMSA also supported a transcriptional regulation of PhgS on the expression of type 3 fimbriae. Nevertheless, a PhgS/PhgM-independent promoter PL-mrk was also identified indicating a complex regulation on the expression of type 3 fimbriae.

Contents

中文摘要………………………………………………………………………. ii
Abstract………………………………………………………………………… iv

Chapter I 1
Introduction…………………………………………………………………….. 2

Chapter II 9
Materials and methods…………………………………………………………. 10

Chapter III
Allelic variation of type 3 fimbrial adhesin MrkD affects the fimbriation and adhesion activity 21
3.1 Abstract.......................................................................................................... 22
3.2 Results and discussion……………………………………………………... 23

Chapter IV
Regulation of expression of type 3 fimbriae in Klebsiella pneumoniae CG43 32
4.1 Abstract…………………………………………………………………….. 33
4.2 Results and discussion……………………………………………………... 34

Chapter V 45
Summary 46

References……………………………………………………………………… 49
Tables………………………………………………………………………….... 64
Figures………………………………………………………………………….. 68

References:
呂文鈴，國立清華大學碩士論文，克雷白氏肺炎菌CG43第三型纖毛黏附因子的鑑定，中華民國九十年六月。

陳美甄，國立交通大學碩士論文，克雷白氏肺炎菌CG43第三型纖毛黏附蛋白特性，中華民國九十一年六月。

廖心瑋，國立交通大學碩士論文，克雷白氏肺炎菌CG43第三型纖毛組成蛋白MrkD與MrkF之功能探討，中華民國九十五年六月。

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