綠膿桿菌PAO1之轉錄因子PsrA於綠膿菌素生合成之調控

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研究生：	廖祐瑄 Liao, Yu-Hsuan
論文名稱：	綠膿桿菌PAO1之轉錄因子PsrA於綠膿菌素生合成之調控 Regulation of pyocyanin biosynthesis by transcriptional regulator PsrA in Pseudomonas aeruginosa PAO1
指導教授：	張晃猷 Chang, Hwan-You
口試委員:	賴怡琪 Lai, Yi-Chyi 林靖婷 Lin, Ching-Ting
學位類別：	碩士 Master
系所名稱：	生命科學暨醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2017
畢業學年度：	105
語文別：	英文
論文頁數：	71
中文關鍵詞：	綠膿桿菌、綠膿菌素、轉錄因子 PsrA
外文關鍵詞：	Pseudomonas aeruginosa, pyocyanin, transcriptional regulator PsrA
相關次數：	點閱：3 下載：0
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綠膿桿菌為一造成院內感染之病原菌。此細菌能產生藍綠色綠膿菌素，為該菌重要毒素之一，可受群體感應影響並對宿主細胞造成氧化壓力而使細胞受損。PsrA 為綠膿桿菌之轉錄因子，在細菌體內調控許多與生理、毒力及群體感應相關的基因表現。而在綠膿桿菌中，PsrA 調控綠膿菌素的生合成機制尚未清楚，因此本研究致力於探討 PsrA 如何調控綠膿桿菌之綠膿菌素生合成。我們藉由轉錄體分析，比較野生株 PAO1 與大量表現 psrA 菌株之綠膿菌素合成相關之調控路徑的基因表現。同時，我們測定大量表現 psrA 菌株及ΔpsrA突變株之綠膿菌素產量、群體感應、胞外多醣產量、溶血活性等，來觀察PsrA對菌體毒性因子表現之影響。結果顯示，psrA 大量表現的菌株，1) 其合成綠膿菌素的前驅物 phenazine 相關之 phz 基因組的表現量較野生株高，綠膿菌素生成量亦較野生株多；2) 群體感應 AHL 訊號分子系統 (LasI/LasR-RhlI/RhlR) 之編碼基因的表現量較野生株低，且以紫色桿菌 CV026 測試細菌 AHL 的產量得知 psrA 大量表現菌株的 AHL 產量明顯較少；3) 受 LasR 正調控之群體感應 quinolone 訊號分子系統 (Pqs) 之編碼基因的表現量上升；4) 降解受質 (彈性蛋白、紅血球、酪蛋白) 的能力皆較野生株弱，且與降解受質蛋白相關的蛋白酶其編碼基因在 psrA 大量表現菌株中的表現量皆下降；5) 生成胞外多醣其中成份 Pel 的編碼基因之表現量上升，且透過剛果紅結合胞外多醣試驗可得知 psrA 大量表現之菌株分泌較多的胞外多醣。除此之外，我們利用 GUS 報導基因系統以了解 PsrA 調控的操縱子。結果顯示，除了已知 PsrA 會調控 rpoS 外，在本研究中我們證實了 PsrA 會調控群體感應 AHL 以及 quinolone 訊號分子系統，但並不會直接調控 phz 操縱子。綜合以上結果，PsrA 可能是透過調節群體感應系統而調節了綠膿菌素的生成量，以及透過調控群體感應系統而影響下游數種毒力因子的表現。本研究除了了解轉錄因子 PsrA 如何調控綠膿菌素的生成，亦提供 PsrA 調控網絡資訊，以全面了解 PsrA 對於綠膿桿菌的生理或致病能力之重要性。

Pseudomonas aeruginosa is a common pathogen that causes nosocomial infections. It can produce pyocyanin, a blue-green pigment, which is one of the major virulence factors in P. aeruginosa. The pigment is known to disrupt host cells by causing oxidative stress. The biosynthesis of pyocyanin is controlled by quorum sensing, which is also regulated by PsrA. PsrA is a transcriptional regulator in P. aeruginosa that regulates the expression of many physiological and virulent-related genes. The aim of this study is to investigate the mechanism of pyocyanin biosynthesis regulation via PsrA in P. aeruginosa. Initially a transcriptome analysis was used to compare the expression level of pyocyanin biosynthesis-related genes of wild-type PAO1 with that of psrA overexpression strain. In addition, the quantity of pyocyanin, quorum sensing autoinducer, exopolysaccharide, and hemolytic activity were determined in the wild-type, psrA overexpression and psrA deletion strains. The result showed that in psrA overexpression strain: 1) the expression of phz operon, responsible for pyocyanin synthesis, increased compared with that of the wild-type PAO1; 2) the expression of AHL quorum sensing system genes was reduced, and also less AHL autoinducer was produced than in wild-type PAO1; 3) the expression of quinolone quorum sensing system (Pqs)-related genes which was positively regulated by LasR was increased; 4) the activity of hydrolytic enzymes, including elastase, hemolysin, caseinase, were lower than wild-type PAO1, so was the expression of their encoding genes; 5) the expression of exopolysaccharide pel was increased and more exopolysaccharide production was observed. Moreover, the use of GUS reporter assay indicates that PsrA regulated AHL quorum sensing system and Pqs quorum sensing system, although PsrA seems to regulate the phz operon. Altogether, these findings contribute to comprehensive understanding of how PsrA regulates pyocyanin biosynthesis and the importance of PsrA on physiology and pathogenesis in P. aeruginosa.

Table of Contents
摘要    I
Abstract    II
誌謝    IV
Abbreviations    V
Table of Contents    VII
List of Tables    X
List of Figures    XI
1. Introduction    1
1.1 General properties of Pseudomonas aeruginosa    1
1.2 Pathogenesis of P. aeruginosa    1
1.3 Pyocyanin property    3
1.4 Biosynthesis of pyocyanin    4
1.5 Quorum sensing    5
1.6 Transcription factor PsrA    7
1.7 Objective of this study    7
2. Materials and methods    9
2.1 Bacterial strains and growth conditions    9
2.2 Cell culture    10
2.3 Quantification of pyocyanin production    10
2.4 N-acyl homoserine lactone assay    11
2.5 Elastase activity assay    11
2.6 Hemolysis activity assay    12
2.7 Caseinase activity assay    12
2.8 Exopolysaccharide production assay    13
2.9 Cytotoxicity assay    13
2.10 Total RNA extraction    14
2.11 DNase I treatment of the RNA preparation    15
2.12 Preparation of cDNA for quantitative real-time PCR analyses    16
2.13 Quantitative real-time PCR analysis    16
2.14 Transcriptome analysis    17
2.15 Genomic DNA extraction    17
2.16 Plasmid DNA extraction    18
2.17 Amplification of DNA fragments    19
2.18 Restriction enzyme digestion    19
2.19 Purification of DNA    20
2.20 Ligation of DNA fragments    20
2.21 Preparation of competent cells    20
2.22 Transformation by heat shock    21
2.23 Bacteria conjugation    21
2.24 β-glucuronidase reporter gene assay    22
3. Results    25
3.1 The psrA overexpression strain produced significantly more pyocyanin than the wild-type PAO1    25
3.2 Quorum sensing was affected by psrA overexpression    25
3.3 The substrate degradation activity and cytotoxicity of psrA overexpression strain were decreased    27
3.4 PsrA promotes exopolysaccharide production    29
3.5 PsrA regulates AHL and quinolone quorum sensing system    30
3.6 PsrA is an important regulator    30
4. Discussion    32
5. References    37
6. Appendices    71
Appendix 1.    The phenazine biosynthetic operons in Pseudomonas aeruginosa PAO1    71


List of Tables
Table 1.    Bacterial strains and plasmids used in this study.    45
Table 2.    Oligonucleotide primers used in this study.    47
Table 3.    Expression levels of pyocyanin biosynthesis-related genes in psrA overexpression strain relative to that of PAO1 [pMMB66EH]    50
Table 4.    Expression levels of secretion system-related genes in psrA overexpression strain relative to that of PAO1 [pMMB66EH]    52
Table 5.    Expression levels of EPS-related genes in psrA overexpression strain relative to that of PAO1 [pMMB66EH]    55
Table 6.    Expression levels of type IV pili-related genes in psrA overexpression strain relative to that of PAO1 [pMMB66EH]    56
Table 7.    Top fifty PsrA up-regulation genes in psrA overexpression strain relative to that of PAO1 [pMMB66EH]    57
Table 8.    Top fifty PsrA down-regulation genes in psrA overexpression strain relative to that of PAO1 [pMMB66EH]    59


List of Figures
Figure 1.    Effects of psrA on pyocyanin production in P. aeruginosa PAO1    61
Figure 2.    Effects of psrA on phzA1B1C1D1E1F1G1 and phzA2B2C2D2E2F2G2 operon gene expression    62
Figure 3.    Effects of psrA on AHL production in P. aeruginosa    63
Figure 4.    Effects of psrA on expression of quorum sensing-related genes    64
Figure 5.    Effects of psrA on elastase, hemolysis, and caseinase activity in P. aeruginosa    65
Figure 6.    Effects of psrA on P. aeruginosa cytotoxicity    67
Figure 7.    Effects of psrA on P. aeruginosa exopolysaccharide production    68
Figure 8.    Effects of psrA on the promoter activity of phzA1, lasR, pqsA, and rpoS.    69
Figure 9.    A model of regulatory function of psrA in PAO1    70
                                

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