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研究生：	黃文俊 Huang, Wen-Chun
論文名稱：	蛋白酶Prc在腸道外致病性大腸桿菌致病機轉的角色 The role of protease Prc in pathogenesis of Extraintestinal Pathogenic Escherichia coli
指導教授：	鄧景浩 Teng, Ching-Hao
學位類別：	博士 Doctor
系所名稱：	醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences
論文出版年：	2016
畢業學年度：	104
語文別：	英文
論文頁數：	104
中文關鍵詞：	Prc蛋白酶、移動力、鞭毛、σE系統、RcsCDB二元系統
外文關鍵詞：	Prc protease, motility, flagella, σE system, RcsCDB two-component system
相關次數：	點閱：105 下載：2
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腸道外致病性大腸桿菌會造成許多腸道外感染的疾病，像是新生兒腦膜炎、菌血症、泌尿道感染。抗生素治療是傳統上治療大腸桿菌感染的方式。然而，抗藥性菌株的迅速崛起已成為控管細菌感染的嚴重問題。因此，急需發展新穎對抗微生物的策略來抵禦大腸桿菌的相關感染。對於細菌造成感染所需要的分子將會是制定這種戰略的潛力目標。細菌周質蛋白酶Prc可能是發展新穎對抗腸道外致病性大腸桿菌感染策略的潛力目標，因為我們的實驗室已經確認腸道外致病性大腸桿菌引起菌血症需要Prc的參與。然而尚未清楚蛋白酶Prc是否有助於腸道外致病性大腸桿菌在其他宿主組織造成的感染。在本研究中，我們揭露剔除prc基因會降低腸道外致病性大腸桿菌引起泌尿道感染的能力。根據蛋白質體分析，在prc基因剔除菌株中，細菌鞭毛的主要成份鞭毛蛋白(FliC)的表現量降低。因此，prc基因剔除菌株也顯示有缺陷的移動能力，並且有缺陷的移動能力是造成prc基因剔除菌株減少菌落殖民在膀胱和腎臟的原因。剔除prc基因會活化兩個細胞質外的信號傳遞系統，σE系統和RcsCDB二元系統。活化的這兩個信號傳遞系統會減少合成鞭毛的主要調節因子FlhDC的轉錄程度，進而降低鞭毛蛋白(FliC)的表現。此外，缺失Prc的蛋白酶功能是造成prc基因剔除菌株移動力缺陷的原因，這表示蛋白酶Prc的受質可能和prc基因剔除菌株缺陷的表型有關。如同預期，在prc基因剔除菌株中，Prc的受質Spr蛋白質的累積現象促使RcsCDB二元系統活化，而造成移動力下降。本研究增加了解蛋白酶Prc在菌血症之外，在腸道外致病性大腸桿菌引起泌尿道感染的角色，並且，證實蛋白酶Prc作為對抗微生物標的潛力角色。

Extraintestinal Pathogenic Escherichia coli (ExPEC) are responsible for many extraintestinal infectious diseases, such as neonatal meningitis, bacteremia, and urinary tract infections (UTIs). Antibiotic therapy is the traditional way to treat E. coli infections. However, the rapid emergence of antibiotic resistant strains have become serious problems to manage the bacterial infections. Therefore, new antimicrobial strategies against the E. coli-associated infections are urgently needed. Bacterial factors required for the pathogens to cause infections will be potential targets for developing such strategies. The periplasmic protease Prc may be a potential antimicrobial target for the development of new strategies against ExPEC infection, because our laboratory has identified that Prc is required for ExPEC to cause bacteremia. However, it remains unclear whether this protease contributes to ExPEC infections in other host tissues. In this study, we revealed that deletion of prc decreased the ability of ExPEC to cause UTIs. Based on the proteome analysis, the major component of the flagellum filament, FliC, was down-regulated in the prc mutant. Therefore, the prc mutant of ExPEC showed defective motility which contributed to the decreased ability to colonize the bladder and kidney. Deletion of prc triggered the activation of two extracytoplasmic signaling pathways, the σE and the RcsCDB systems. The activation of the systems downregulated the transcription of flhDC, which encode the master regulator of flagellar biosynthesis, and thus suppressed the expression of fliC. In addition, the lack of the Prc protease function was found be responsible for the defective motility of the prc mutant, suggesting that the substrate of this protease may be involved in the defective phenotype of the mutant. As expected, accumulation of the known Prc substrate Spr in the prc mutant was shown to contribute to the activation of RcsCDB system, and thus to suppress the bacterial motility. This study strengthens an alternative role of Prc in the ExPEC UTIs, other than the ExPEC bacteremia, and substantiates the potential role of Prc as an antimicrobial targets.

中文摘要	I
Abstract	II
誌謝	IV
Contents	VI
List of Tables	X
List of Figures	XI
Abbreviations	XIII
Introduction	1
1 The pathogenic Escherichia coli and E. coli-associated infections	1
1.1 The types of pathogenic E .coli	1
1.2 ExPEC associated infections in human	2
1.3 The features of the ExPEC strains used in this study	3
2 Antibiotic therapy and the problem of antibiotic resistant strain	4
3 Potential antimicrobial targets in the bacterial pathogens	5
4 Introduction of protease Prc	6
4.1 Characterization of prc	6
4.2 Prc and its homologs contribute to bacterial pathogenesis	6
4.3 The defective phenotypes caused by the deletion of prc	7
4.4 The functional domain of Prc	8
4.5 The known substrates of Prc	9
5 Introduction of flagella	10
5.1 Flagellum is an important virulence factor of bacterial pathogenesis	10
5.2 The flagellar regulon	10
5.3 The extracytoplasmic signals controlling flagellar regulon	11
6 The extracytoplasmic stress response systems	12
6.1 The activation of σE system	13
6.2 The activation of two-component system RcsCDB system	14
Specific Aims	15
Materials and methods	16
1 Bacterial strains, plasmids and growth condition	16
2 Construction of deletion mutants	16
3 Construction of recombinant plasmids	16
4 Urinary tract infection model	17
5 Motility assay	17
6 Analysis of the genes expression and RNA-Seq	18
6.1 RNA isolation	18
6.2 RNA sequencing and identification of differentially expressed genes	19
6.3 The complementary DNA synthesis	19
6.4 Real-time PCR (qPCR) and Reverse transcription-PCR (RT-PCR)	20
7 Purification of total bacterial proteins, outer membrane proteins and Liquid chromatography-tandem mass spectrometry (LC/MS/MS) analysis	20
8 Western blot analysis	22
9 Construction of strains with spr-3XFlag at the chromosomal locus.	22
10 Statistical analysis	23
Results	24
1 Deletion of prc in the Extraintestinal Pathogenic Escherichia coli (ExPEC) decreased the pathogen’s ability to colonize the bladder and kidney in the mouse model of urinary tract infection (UTI).	24
2 Identification of the outer membrane proteins whose expression were affected by deletion of prc.	24
3 Deletion of prc decreased the flagellin expression and motility of ExPEC.	25
4 The protease function of Prc was required for the bacterial motility and FliC expression.	26
5 Deletion of prc decreased the expression of the flagellar regulons.	26
6 Deletion of prc decreased the FliC expression and bacterial motility by suppressing the expression of the flhDC operon.	27
7 The defective motility was responsible for the defect of Δprc mutant in urinary tract infection.	27
8 Deletion of prc may activate five extracytoplasmic signaling pathways.	28
9 Blocking the activation of the σE or RcsCDB systems partially restored the decreased motility of the prc mutant of ExPEC.	29
10 The activation of σE and RcsCDB systems were involved in suppression of FliC expression and flhDC transcription in Δprc-RS218.	30
11 The activated σE system suppressed motility and the flhDC transcription.	30
12 The σE and RcsCDB systems worked independently to regulate the bacterial motility.	31
13 The accumulation of Spr contributed to defective motility and FliC expression of Δprc-RS218 through activating the RcsCDB system.	32
14 Deletion of prc decreased the bacterial motility and FliC expression through other manner independent of FlhDC.	33
15 The activated σE and RcsCDB systems decreased the bacterial motility and FliC expression through other manner independent of FlhDC.	33
Discussion	35
Tables	41
Figures	59
References	86


                                    

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