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研究生：	江倪全 Chiang-Ni, Chuan
論文名稱：	A 群鏈球菌熱原性外毒素 B 之致病機制及其在轉錄層次所受到之調控 Transcriptional Regulation and Pathogenesis Mechanisms for Streptococcal Pyrogenic Exotoxin B of Streptococcus pyogenes
指導教授：	吳俊忠 Wu, Jiunn-Jong
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：	2009
畢業學年度：	97
語文別：	英文
論文頁數：	124
中文關鍵詞：	致病機制、熱原性外毒素 B 、A 群鏈球菌
外文關鍵詞：	regulation, pathogenesis, covR, speB, group A streptococcus
相關次數：	點閱：68 下載：4
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A 群鏈球菌為革蘭氏陽性人類致病菌，能引起細菌性咽喉炎以及具有高致死率之壞死性肌膜炎和鏈球菌毒性症候群等疾病。熱原性外毒素 B (SpeB) 為 A 群鏈球菌重要之毒力因子之一，目前已知和感染時的組織損傷，細菌逃脫被免疫反應所清除，及細菌存活於血液中有關。 SpeB 為半胱胺酸蛋白，能切除或分解宿主之胞外基質、免疫球蛋白、補體、甚至細菌菌體表面之附著因子其及分泌之蛋白質。在 A 群鏈球菌中，SpeB 的表現侷限於生長曲線之靜止期並由許多轉錄調控因子所調控。然而，控制 SpeB 表現的調控網路到目前為止尚未被詳細的描述。本論文有兩個主要的研究主題，包括分析 SpeB 在 A 群鏈球菌存活於人類血液中所扮演的角色，以及 A 群鏈球菌調控 SpeB 表現之調控網路。我們發現野生株在全血中的存活率為 speB 突變株之 5-20 倍。進一步的分析發現 SpeB 可能會透過造成多核性白血球之粒腺體損傷而使得多核性白血球無法有效的清除細菌而讓細菌能存活於全血中以造成進一步的感染。另一方面，我們藉由分析 SpeB 調控因子在不表現 SpeB 臨床菌株中之表現模式，以及 Rgg (SpeB 正向調控因子) 和 CovR (SpeB 負向調控因子) 在不同生長時期之表現以了解 SpeB 之調控網路。結果顯示，不表現 SpeB 臨床菌株會喪失表現 speB RNA 及驅動 speB 啟動子的能力，暗示 SpeB 的調控因子扮演重要的角色，進一步的分析顯示目前已知的 SpeB 調控因子之表現模式在正常表現 SpeB 或不表現 SpeB 之菌株間並沒有顯著的差異。在分析 rgg 及 covR 表現模式方面，雖然所有已分析的菌株之 rgg 均在靜止期的早期表現，然而 covR 的表現模式在不同菌株間卻不相同。有 52% 已分析菌株之 covR 在對數期表現，而有 48% 之菌株之 covR 則在靜止期的早期表現。進一步的分析顯示，covR 在靜止期的早期表現之菌株有較好的細菌生長活性、較早的 SpeB 表現、及與 A 群鏈球菌分型 emm1/ST28 有顯著的相關性，而 covR 在對數期表現的菌株則無此現象。除此之外，我們也發現在 covR 基因下游有二段轉錄中止序列能中止 covR/S operon (2.5-kb) 的轉錄而產生 covR monocistronic transcripts (1.0-kb 及 0.8-kb)。綜合前述，本研究的結果顯示在 A 群鏈球菌感染時，SpeB 可能會透過造成多核性白血球粒腺體損傷以逃避其清除；此外，SpeB 調控因子分析的結果顯示，A 群鏈球菌不僅具有複雜的 SpeB 調控網路，而且在不同菌株間也可能有不同的調控機制。

Group A streptococcus (GAS) is a gram-positive human pathogen responsible for wide spectrum of diseases including pharyngitis, necrotizing fasciitis and streptococcal toxic shock syndrome. Streptococcal pyrogenic exotoxin B (SpeB) is one of the important virulence factors of GAS. It is a cysteine protease which cleaves or degrades host extracellular matrix, immunoglobulins, complement components, and even GAS surface adhesins and secreted proteins. SpeB expression is restricted at the stationary phase of growth and tightly regulated by GAS through several transcriptional regulators. However, the regulatory network of SpeB is unclear. In this thesis, we analyzed the effects of SpeB for GAS survival in human whole blood and the regulatory network of SpeB. We showed the speB mutants have five to twenty-fold decreases of survival in human whole blood when compared with the wild-type strains. Further analysis showed that SpeB might cause the polymorphonuclear (PMN) cells mitochondria damage to inactivate PMN cells phagocytic activity. To clarify the regulatory network of SpeB in GAS, we analyzed the SpeB regulatory genes expression pattern in clinical isolated SpeB non-secretors and the temporal expression during growth phases of two important SpeB regulators, Rgg (positive regulator of SpeB) and CovR (negative regulator of SpeB). Our results showed SpeB non-secretors cannot transcribe speB and drive speB promoter, suggesting that the transcriptional regulators were involved. However, RNA expression pattern of five well-known SpeB transcriptional regulators did not have the significant difference when compared with that of the SpeB secretors. In other aspect, the Northern hybridization analysis showed that rgg expression is restricted at early-stationary phase, whereas, covR expression pattern during bacterial growth is different among GAS strains. We found 58% and 42% of analyzed strains expressed covR at exponential phase and early-stationary phase of growth, respectively. Further analysis showed that strains with covR expression at early-stationary phase are correlated with better growth activity, earlier SpeB expression, and emm1/ST28 type, but not strains with covR expression at exponential phase of growth. In addition, we also identified two RNA transcriptional terminator sequences downstream of the covR gene which can terminate covR/S operon (2.5-kb) transcription and generate covR monocistronic transcripts (1-kb and 0.8-kb). In conclusion, our results showed SpeB might cause PMN cell’s mitochondria damage to help bacteria evading from immune clearance and also revealed the complexity and diversity of the SpeB regulatory network in GAS.

Table of contents
中文摘要  ······················· ··· i
Abstract ··························· ii
致謝  ···························· iii
Table of contents  ······················   iv
List of tables  ······························ viii
List of figures  ························ ix
Abbreviations  ························ xi
1.  Introduction························ 1
2.  Materials and methods
2.1.  Bacterial strains, plasmids, and culture conditions  ······· 18
2.2.  Cell lines and cell culture conditions  ·············18
2.3.  DNA manipulations
2.3.1.  E. coli
2.3.1.1.  Plasmid DNA extraction  ················18
2.3.1.2.  Competent cell preparation  ···············19
2.3.1.3.  Heat-shock transformation················19
2.3.2.  Group A streptococcus
2.3.2.1.  Genomic DNA extraction  ················20
2.3.2.2. Plasmid DNA extraction  ·················20
2.3.2.3.  Competent cell preparation  ···············20
2.3.2.4.  Electroporation  ····················21
2.3.2.5.  Southern hybridization
2.3.2.5.1. DNA digestion and electrophoresis  ············21
2.3.2.5.2. DNA transfer  ·····················21
2.3.2.5.3. Hybridization  ·····················22
2.4.  RNA manipulations
2.4.1.  Reverse transcription polymerase chain reaction (RT-PCR) ····23
2.4.2.  E. coli
2.4.2.1.  RNA extraction  ····················23
2.4.3.  Group A streptococcus
2.4.3.1.  RNA extraction  ····················23
2.4.3.2.  Northern hybridization and RNA dot blot analysis
2.4.3.2.1. RNA preparation  ···················24
2.4.3.2.2. Agarose-formaldehyde gel preparation  ··········24
2.4.3.2.3. RNA electrophoresis and transfer  ············24
2.4.3.3. RNA stability assay  ··················25
2.4.3.4. RNA transcriptional terminator sequences and RNA secondary structure predictions  ·····················25
2.5.  Molecular typing of group A streptococcus ··········25
2.6.  Protein manipulations
2.6.1. Sodium dodecyl sulfate polyacrylamide (SDS-PAGE) electrophoresis ·······························26
2.6.2.  Protein concentration measurement  ·············26
2.6.3.  Western hybridization  ··················27
2.6.4.  Recombinant CovR protein purification  ···········27
2.6.5.  Mouse anti-CovR serum preparation  ············27
2.6.6.  Group A streptococcus total protein extraction  ········28
2.6.7.  Culture supernatant total protein precipitation  ········28
2.7.  Group A streptococcus phenotypic characteristics
2.7.1.  Growth curve  ·····················29
2.7.2.  Hyaluronic acid capsule content  ··············29
2.7.3.  Promoter activity- Luciferase activity assay  ·········29
2.7.4.  SpeB protease activity
2.7.4.1.  Skim-milk agar assay  ··················30
2.7.4.2.  Azocasein assay  ····················30
2.8.  Cell manipulations
2.8.1.  Phagocytosis assay  ···················30
2.8.2.  Determination of polymorphonuclear (PMN) cell numbers  ····31
2.8.3.  Measurement of PMN cell metabolic activity  ·········31
2.8.4.  Measurement of mitochondria integrity
2.8.4.1  Measurement of mitochondria dehydrogenase activity ·····31
2.8.4.2.  Measurement of mitochondria membrane potential  ······32
2.9.  Statistics  ························32

3.  Results
3.1. SpeB prevents phagocytosis of group A streptococcus via causing mitochondria damage of polymorphonuclear cells
3.1.1.  Confirmation of the speB isogenic mutant  ··········33
3.1.2.  SpeB is important for group A streptococcus survival in human whole blood  ·························33
3.1.3.  SpeB inactivates the metabolic activity of polymorphonuclear (PMN) cells  ····························34
3.1.4.  SpeB causes mitochondria damage in PMN cells  ·······34
3.1.5.  SpeB expression in A-549 cells  ··············35
3.2.  Molecular characterization of SpeB non-secretor group A streptococci
3.2.1.  Microbiological characterization of SpeB non-secretor isolates  ··35
3.2.2.  SpeB non-secretors have no speB transcription  ········ 36
3.2.3. The nucleotide sequence analysis of the speB gene in SpeB non-secretors  ························36
3.2.4.  SpeB non-secretors cannot drive the speB promoter  ······36
3.2.5.  The RNA transcription of rgg, covR, mga, pel, and opp in SpeB non-secretors  ························37
3.3.  Temporal regulation of SpeB
3.3.1. rgg and covR RNA expression pattern during bacterial growth phases  ··························· 37
3.3.2.  covR expression in wild-type and rgg over-expression strains ·· 38
3.4.  The transcriptional terminator sequences of the covR gene terminate covR/S operon transcription and generate monocistronic covR transcripts  
3.4.1.  Analysis of RNA transcript of the covR/S operon  ·······39
3.4.2.  Transcriptional terminator sequences prediction  ·······39
3.4.3.  Determination of the 3’ transcription terminators of the covR gene·····························40
3.4.4.  The terminator sequences terminate covR/S operon transcription in E. coli background  ······················· 40
3.5.  Terminator sequences have potential regulatory activity
3.5.1.  Expression of terminator sequence 1-2 extrachromosomally affects the native covR/S operon transcription  ··············41
3.5.2.  Expression of the covR gene with terminator sequence 1-2 represses bacterial growth activity  ····················41
3.5.3.  Mutation of the covR promoter ribosome-binding site and covR gene start codon did not abolish CovR protein expression  ········42
3.5.4.  CovR protein expression is required for growth activity repression··························42
3.5.5.  SpeB is not regulated by CovR in NZ131  ··········43
3.6.  Two covR expression patterns are associated with bacterial growth activity to modulate virulence genes expression in group A streptococcus
3.6.1.  Two different covR expression patterns are presented among group A streptococci  ························43
3.6.2. Different covR expression pattern is correlated with different bacterial growth activity ························44
3.6.3.  The speB, sagA, emm, and scpA genes expression in covR-E and covR-S strains  ························44
3.6.4. Multi locus sequence typing (MLST) and pulsed field gel electrophoresis (PFGE) dendrogram analysis ············45
4.  Discussion  ························47
5.  References  ························ 59
6.  Tables  ··························80
7.  Figures  ·························89
8.  Appendix
8.1.  Reference figures  ····················116
8.2.  Media and Solutions  ···················118
8.3.  Chemicals and Reagents  ·················122
9. 自述  ··························124
 
List of Tables
Table 1.  ·························· 80
The primers used in this study
Table 2.  ·························· 82
The vectors and recombinant plasmids used in this study
Table 3.  ·························· 84
The group A streptococcus strains used in this study
Table 4.  ·························· 85
The emm type, presence of speB gene, speB RNA expression, and resulting diseases of SpeB non-secretors 
Table 5.  ·························· 86
The polymorphic sites within the 939 bp upstream of non-coding region and 1197 bp coding region of the speB gene
Table 6.  ·························· 87
The emm type, PFGE type, covR expression pattern, and resulting diseases of group A streptococcus isolates
 
List of Figures
Fig. 1  ··························· 89
Construction of SW117 speB isogenic mutant.
Fig. 2  ··························· 90
The effects of SpeB on the survival of wild-type strains and speB mutants in human whole blood and plasma.
Fig. 3  ··························· 91
The metabolic activity of PMN cells infected by wild-type strain and speB mutant.
Fig. 4  ··························· 92
The mitochondria integrity of r-SpeB or r-C192S treated PMN cells.
Fig. 5  ··························· 93
The speB expression pattern of NZ131 in A-549 cell and culture broth.
Fig. 6  ··························· 94
The speB expression of SpeB non-secretors in normal or acid broth culture condition.
Fig. 7  ··························· 95
The speB promoter activity of SpeB non-secretors.
Fig. 8  ··························· 96
The expression levels of speB transcriptional regulators in SpeB non-secretors.
Fig. 9  ··························· 98
Temporal expression of rgg, covR, and speB in A-20, SW117, and NZ131.
Fig. 10  ··························· 99
covR/S transcription in rgg over-expression strains.
Fig. 11  ·························· 100
Detection of covR/S operon mRNA in A-20, SF370, SW117, and NZ131.
Fig. 12  ·························· 101
The location of the predicted rho-independent terminator sequences of covR.
Fig. 13  ·························· 102
The terminator activity of the predicted terminator sequences downstream of covR.
Fig. 14  ·························· 103
The terminator activity of the predicted terminator sequences of covR in E. coli background.
Fig. 15  ··························  104
Detection of the covR/S operon mRNA in NZ131 with over-expression of terminator sequences.
Fig. 16  ·························· 105
The growth curves of covR mutant and CovR complementation strains.
Fig. 17  ·························· 106
CovR protein expression and the growth curve of SW619 and SW620.
Fig. 18  ·························· 107
CovR protein expression and the growth curve of SW630, SW632 and SW633.
Fig. 19  ······························ 108
SpeB expression in NZ131, SW616, SW619 and SW620.
Fig. 20  ·························· 109
The covR expression patterns among group A streptococci.
Fig. 21  ······························ 111
The growth curves of strains with different covR expression patterns.
Fig. 22  ·························· 112
The expression patterns of speB, sagA, emm, and scpA in SF370 and NZ131.
Fig. 23  ·························· 113
The expression patterns of speB, sagA, emm, and scpA in A-20 and GAS516.
Fig. 24  ·························· 114
MLST-based dendrogram of group A streptococcus isolates and their ST and emm types.
Fig. 25  ······························ 115
Dendrogram and PFGE patterns of SmaI digested chromosomal DNA of group A streptococcus isolates.
                                    

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