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研究生:鄭榆婷
研究生(外文):Yu-Ting Cheng
論文名稱:馬賽分枝桿菌臨床菌株R49R與R49S之特性研究
論文名稱(外文):Characterization of Mycobacterium massiliense clinical strains: R49R and R49S
指導教授:胡小婷
指導教授(外文):Shiau-Ting Hu
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:微生物及免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:英文
論文頁數:82
中文關鍵詞:馬賽分枝桿菌菌落型態轉變
外文關鍵詞:Mycobacterium massiliensemorphological change
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膿瘍分枝桿菌複合菌群(Mycobacterium abscessus complex)屬於非結核型快速生長分枝桿菌,可在人體多種部位造成感染,並具有抗藥性。根據RNA聚合酶次單元的DNA序列可再細分為膿瘍分枝桿菌(M. abscessus)、馬賽分枝桿菌(M. massiliense)以及Bolletti分枝桿菌(M. bolletti)。先前文獻指出膿瘍分枝桿菌具有粗糙和平滑二種菌落型態,與致病能力有關;粗糙型較具毒性且引起較嚴重的疾病。膿瘍分枝桿菌可轉換自身型態,型態的改變與細胞壁上的醣類胺基酸脂質鍵結物(glycopeptidolipid, GPL)含量有關,平滑型具有較多的GPL。本篇研究中,從同一病人身上同時分離出的R49R(粗糙型)和R49S(平滑型)馬賽分枝桿菌具有高度同源性,並展現非常不同的性狀。R49R會緊密黏附於塑膠管壁上且具有很強的聚集能力,但無法滑行於半固體培養基上,而R49S則具有較強的滑行能力並且細胞壁上含有大量的GPL。序列比對發現位於GPL基因座上的基因序列並無差別,但是R49R缺乏長達54 kb的DNA,此54 kb DNA簡稱R49-RD。R49-RD兩端具有含19個核甘酸同向的重複序列,並預測含有58個開放讀碼區(open reading frame, ORF),包括和脂質合成代謝相關的基因、轉錄調節因子以及基因重組酶(ORF058)。我們認為R49-RD之刪除有可能是由ORF058所導致並造成型態變異,但需後續之研究加以證實。
Mycobacterium abscessus complex belongs to the rapidly growing mycobacteria, which is resistant to most antibiotics and causes wide spectrum of infections. This complex recently been classified into three subspecies, M. abscessus sensu stricto, M. massiliense and M. bolletti based on the sequence of rpoB. Previous studies indicated that M. abscessus can spontaneously switch morphotype between rough and smooth forms, which are considered to be associated to glycopepetidolipid (GPL) expression and different morphologies that may affect bacteria virulence in human. In our study, clinically isolated M. massiliense from the same patient contained rough and smooth forms, named R49R and R49S, respectively, that had highly similar restriction enzyme digestion patterns. We found that R49R attached intensively to the surface of the plastic tube compared to other strains and had strong aggregation ability and lacked sliding ability. The GPL contents of R49S were significantly higher than that of R49R, but the sequences of GPL-locus genes are identical. Whole genome sequences analysis and comparison showed a 54-kb deletion within R49R genome. The 54-kb region of difference between R49R and R49S (R49-RD) is flanked with 19-mer direct repeats and comprises of 58 open reading frames (ORFs) with predicted functions including lipid biosynthesis/metabolism, transcriptional regulators and recombinase. Whether the deletion of R49-RD resulted from natural recombination and causing morphotype switch remains to be studied.
Contents
摘要 i
Abstract ii
Contents iii
List of Tables vi
List of Figures vii
Chapter 1 Introduction 1
1.1 Mycobacteria 1
1.2 Rapidly Growing Mycobacteria 1
1.3 Mycobacterium abscessus Complex 2
1.3.1 Identification of M. abscessus Subspecies 3
1.3.2 Mycobacterium massiliense 5
1.4 Colony Morphological Variation in NTM 6
1.4.1 Colony Morphological Variation in Mycobacterium smegmatis 6
1.4.2 Colony morphological Variation in Mycobacterium abscessus Complex 6
1.5 Glycopeptidolipid (GPL) 8
1.6 Site-Specific Recombination 10
1.6.1 Tyrosine Recombinase 10
1.6.1.1 Cre-LoxP System 11
1.6.2 Serine Recombinase 11
1.6.2.1 Phage Rv1 Integrase 12
1.7 Rationals and Aims 12
Chapter 2 Materials and Methods 14
2.1 Bacterial strains and culture condition 14
2.2 Primers and plasmids 14
2.3 Plasmid construction 14
2.3.1 Polymerase chain reaction (PCR) 14
2.3.2 DNA purification 15
2.3.3 DNA digestion 15
2.3.4 DNA ligation 16
2.3.5 Plasmid extraction 16
2.3.6 pVV16-rec 16
2.3.7 pET29b(+)-rec 17
2.3.8 pQE80L-rec 17
2.3.9 pCC1BAC NotI-DR-lacZ 17
2.4 Preparation of competent cell 17
2.4.1 Heat shock transformation competent cell (E. coli) 17
2.4.2 Electroporation competent cells 18
2.5 Transformation 18
2.5.1 Heat-shock transformation 18
2.5.2 Electroporation transformation 18
2.6 Protein expression of E. coli and M. massiliense 19
2.7 Western blot 20
2.7.1 Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) 20
2.7.2 Transfer 20
2.7.3 Antibody probed 20
2.7.4 Chemiluminescent detection 21
2.8 Sliding motility test 21
2.9 Aggregation capability assay 21
2.10 Growth curve measurement 22
2.11 Lipid analysis 22
2.11.1 Lipid extraction 22
2.11.2 Lipid saponification 22
2.11.3 Thin-layer chromatography 23
2.12 Determination of mRNA levels 23
2.12.1 RNA extraction 23
2.12.2 Reverse transcription polymerase chain reaction (RT-PCR) 24
2.12.3 Quantitative real-time polymerase chain reaction (qRT-PCR) 24
2.13 Extraction of mycobacteria genomic DNA 25
2.14 Bioinformatic analysis 26
Chapter 3 Result 27
3.1 Identification of M. massiliense clinical strains R49R and R49S 27
3.2 The cell surface property of R49R and R49S 27
3.3 Aggregation ability of R49R and R49S 28
3.4 GPL expression of R49R and R49S 28
3.5 Whole genome sequence alignment of R49R and R49S 29
3.6 The bioinformatics analysis of R49-RD 29
3.7 The over expression of the ORF 058 in M. massiliense R49S and E. coli 30
Chapter 4 Discussion 32
References 37
Appendices 69
Appendix. I Differentiation of M. abscessus complex by duplex PCR 69
Appendix. II Diagram of the structure of GPL, non-specific GPL and serovar specific GPL 70
Appendix. III Genetic structure of GPL locus in M. smegmatis, M, abscessus and M. avium 71
Appendix. IV Diagramof GPL and genes involved in GPL biosynthesis 72
Appendix. V Diagram of recombination mechanisms by tyrosine recombinase 73
Appendix. VI Diagram the Cre-loxP-mediated recombination 74
Appendix. VII Diagram of recombination mechanisms by serine recombinase 75
Appendix. VIII The recombination sites of Rv1 integrase 76
Appendix. IX Identification of R49R and R49S 77
Appendix. X Different M. abscessus strains cultured in plastic tube 78
Appendix. XI Aggregates of R49R protect against the antibiotics 79
Appendix. XII The alignment of lsr2 and mab_3168c 81
List of Tables
Table 1. Bacteria strains used in this study 45
Table 2. Oligonucleotide primers used in this study 46
Table 3. RT primers used in this study 47
Table 4. Plasmids used in this study 49
Table 5. Antibodies used in this study 51
Table 6. Genomic characterization of R49R and R49S 52
Table 7. BLAST of 58 ORFs within R49-RD 53
List of Figures
Fig. 1 Colony morphologies and identification of R49R and R49S 56
Fig. 2 Different cell surface of R49R and R49S 57
Fig. 3 Aggregation ability and growth rate of R49R and R49S 58
Fig. 4 The GPLs expression and GPL locus genes quantitative RT-PCR of R49R and R49S 59
Fig. 5 54-kb region of difference between R49R and R49S (R49-RD) 60
Fig. 6 The bioinformatics analysis of R49-RD 63
Fig. 7 The construct of ORF 058 and the protein detection 65
Fig. 8 The over-expression of the ORF 058 in M. massiliense R49S 67
Fig. 9 The construction of pCC1BAC NotI-DR-lacZ 68



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