綠膿桿菌PAO1的含組氨酸磷酸轉移蛋白B（HptB）能透過PA3346、PA3347、FlgM所組成的夥伴交換系統調控群體泳動。hptB突變株失去群泳能力，但仍可觀察到鞭毛存在。此群泳能力的喪失可以經由過量表達具降解環狀雙鳥嘌呤單磷酸(c-di-GMP)能力之磷酸二酯酶PA2133或PA4367得到一定程度的恢復。本研究致力於探討FliA在HptB調控細菌群泳的路徑中扮演的角色。本研究首先構築fliA剔除株，並於該突變株分別過量表達fliA、PA2133、PA4367。結果顯示，當細菌之fliA被剔除後，細菌失去群泳能力，但在PA2133或PA4367過量表達的情況下可以得到一定程度的恢復，與hptB突變株的情況相似。當fliA基因過量表達時，也會降低游泳及群泳能力。以穿透式電子顯微鏡觀察細菌形態，發現fliA剔除株無鞭毛，而過量表達fliA基因之菌株其鞭毛較野生株之鞭毛明顯變短。轉錄體分析結果顯示，參與鞭毛結構合成及與磷酸二酯酶相關之部分基因表現在fliA基因剔除株較野生株高，但在過量表達fliA之菌株則為下降。以β-葡萄糖苷酸酶報導基因系統確認磷酸二酯酶基因PA4367及PA5017的啟動子活性，結果顯示fliA剔除會導致PA4367啟動子之活性顯著上升，而PA5017啟動子之活性則無明顯變化。透過綠色螢光蛋白報告系統檢測細菌體內c-di-GMP濃度，發現c-di-GMP會在fliA剔除時上升，與轉錄體分析之結果相符。本研究證實了參與在HptB調控細菌群泳路徑中之FliA，其透過調控鞭毛合成以及調節c-di-GMP濃度進而影響細菌群泳之能力，其中PA4367可能為參與在此調控路徑之磷酸二酯酶。於本研究中發現FliA亦影響毒性相關生物特性。我們的研究結果增進了對綠膿桿菌群泳能力調節路徑的瞭解，為未來對轉錄因子FliA的研究提供了新方向。

The histidine-containing phosphotransfer protein-B (HptB, PA3345) regulates swarming motility in Pseudomonas aeruginosa PAO1 through a partner-switching mechanism involving PA3346 (Ser/Thr protein kinase/phosphatase), PA3347 (anti-σ28 factor antagonist), and anti-σ28 factor FlgM. The ΔhptB mutant is defective in swarming, although its flagellum remains intact. Overexpression of PA2133 and PA4367, both encode a c-di-GMP phosphodiesterase (PDE), could rescue the swarming defect of the ΔhptB. To investigate whether σ28 (FliA) regulates P. aeruginosa motility through modulating c-di-GMP level, this study generated a fliA-deletion mutant and a fliA overexpressing stain. The deletion of fliA resulted in a decreased swarming motility which could be partially restored by overexpressing either PA2133 or PA4367. Surprisingly, overexpressing fliA also led to defective swimming and swarming, suggesting that an optimal concentration of FliA is essential for the bacterium to achieve the highest motility. Using transmission electron microscope to examine the bacterial morphology has revealed that ΔfliA had no flagella, and the flagella of the fliA overexpressing strain were significantly shorter than that of wild-type. Transcriptome profiling of PAO1 and ΔfliA showed that the expression levels of several flagella biogenesis and PDE genes decreased in the ΔfliA strain. Further analysis the promoter activity of the PDE genes using the GUS reporter assay confirmed that the activity of PA4367 promoter was indeed decreased in ΔfliA. Finally, this study demonstrated that the intracellular concentration of c-di-GMP was increased in the ΔfliA strain as determined using a GFP-based c-di-GMP reporter system. These findings suggest that FliA participates in HptB-mediated swarming regulation through both affecting flagella biogenesis and modulating c-di-GMP levels. Altogether our findings contribute to a better understanding of how the HptB partner switching system cooperates with FliA to regulate bacterial motility, an important pathogenesis feature of P. Aeruginosa.

中文摘要 I
Abstract II
誌謝 III
Abbreviations IV
Table of Contents VI
List of Figures X
List of Tables XI
1 Introduction 1
1.1 Pseudomonas aeruginosa 2
1.2 Flagella-mediated motility of P. aeruginosa 3
1.3 Two-component system and HptB participate in regulation on swarming motility of P. aeruginosa 3
1.4 FliA, sigma factor 28 (σ28) 5
1.1 C-di-GMP in regulation of motility 6
1.5 Objective of the study 8
2 Materials and Methods 9
2.1 Bacterial strains and plasmids 10
2.2 Bactrial storage and growth conditions 10
2.3 Bioinformatics analysis 11
2.4 Genomic DNA Isolation 11
2.5 Plasmid DNA isolation 13
2.6 Amplification of DNA fragments 14
2.7 Restriction enzyme digestion 14
2.8 Purification of DNA 15
2.9 Ligation of DNA fragments 16
2.10 Preparation of total RNA 16
2.11 Agarose gel electrophoresis 17
2.12 Quantification of DNA and RNA 18
2.13 Preparation of competent cells 18
2.14 Transformation 19
2.15 Conjugation 20
2.16 Construction of P. aeruginosa PAO1 fliA deletion mutant 21
2.17 RNA-seq analysis 22
2.18 Gene reporter assay 22
2.19 Flagella observation by transmission electron microscopy (TEM) 24
2.20 Growth rate 25
2.21 Swarming motility assay 25
2.22 Swimming motility assay 26
2.23 Biofilm formation assay 26
2.24 Caseinase activity assay 27
2.25 Hemolysis assay 28
2.26 Quantification of phenazine pigment production 28
2.27 C-di-GMP reporter assay 29
2.28 Inter-bacterial competition assay 30
2.29 Quorum sensing (QS) signal N-Acyl homoserine lactones (AHL) assay 31
3 Results 32
3.1 The growth rates of P. aeruginosa PAO1 [pMMB66EH], ΔfliA [pMMB66EH], ΔfliA [pMMBfliA], and PAO1 [pMMBfliA] 33
3.2 FliA regulates swimming and swarming motility 33
3.3 FliA regulates biofilm formation 34
3.4 FliA controls the biogenesis of flagella 35
3.5 FliA affects intracellular concentration of c-di-GMP 36
3.6 PA4367 participates in the FliA-mediated regulation of c-di-GMP and swarming motility 37
3.7 FliA regulates phenazine pigment production, hemolysis activity, caseinase activity, quorom sensing, inter-bacterial competition activity, type six secretion system (T6SS), amino acid transport and metabolism, energy production and conversion, and inorganic ion transport and metabolism 38
4 Discussion 44
References 52

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