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系統識別號 U0026-2107201516575100
論文名稱(中文) 探討化膿性鏈球菌的CRISPR-cas系統與emm分型和紅黴素感受性之關係
論文名稱(英文) Relationship of CRISPR-cas system with emm typing and erythromycin susceptibility in Streptococcus pyogenes
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 103
學期 2
出版年 104
研究生(中文) 鄭伯忻
研究生(英文) Po-Xing Zheng
學號 S58981109
學位類別 博士
語文別 英文
論文頁數 121頁
口試委員 指導教授-吳俊忠
口試委員-何漣漪
召集委員-鄧景皓
口試委員-莊偉哲
口試委員-張傳雄
口試委員-郭志鴻
中文關鍵字 化膿性鏈球菌  紅黴素  分子流行病學  CRISPR 
英文關鍵字 Streptococcus pyogenes  erythromycin  molecular epidemiology  CRISPR 
學科別分類
中文摘要 CRISPR是細菌抵抗外來序列的後天免疫系統。由於CRISPR高度變異的特徵,因此相當適合用於研究分子流行病學。化膿性鏈球菌是人類的主要致病菌,它帶有兩組CRISPR系統,包含CRISPR01和CRISPR02。本研究主要目的之一是研究在高盛行emm血清型的菌株中,cas基因組和CRISPR的分布狀況。此外,因為抗藥基因多半位於外來序列上,本研究的第二目的是探討紅黴素感受性和CRISPR之間的關聯性。在第一部分研究中,探討包含emm1、emm3、emm4、emm12及emm28血清型共332株菌株,其CRISPR和cas基因組在兩套CRISPR系統的存在率。研究顯示所有菌株都至少帶有一套CRISPR或cas基因組,且超過90%的間格序列僅專一存在單一種emm血清型。以Simpson’s變異指數和Wallace校正參數分析CRISPR和emm血清型之間的關聯,顯示CRISPR01型和emm血清型有高度相關,而CRISPR02也和emm血清型單方向一致。這些結果皆顯示CRISPR可以作為分析emm血清型的另種方法。在第二部分研究中,我以1997-2003年分離自成大醫院共330株化膿性鏈球菌的紅黴素感受性來分析。這些菌株共有29種emm血清型,其中僅有emm12、emm75、emm92菌株的紅黴素感受性顯著發生改變。分析這些菌株的兩套CRISPR系統的間格序列,顯示間格序列組合與抗藥性高度相關,且帶有較少間格序列的菌株,對紅黴素抗性較高。此外,在抗藥性無顯著改變的emm4菌株中,其間格序列組合或數量與紅黴素抗藥性無關。這研究指出在A群鏈球菌中,CRISPR和抗藥性存在新穎的關聯性。綜合本研究,這些證據皆指出CRISPR可作為化膿性鏈球菌的分子流行病學指標。
英文摘要 Clustered regularly interspaced short palindromic repeats (CRISPR) are the bacterial adaptive immune system against the foreign nucleic acid. Given the variable nature of CRISPR, it would be a good marker for molecular epidemiology. Streptococcus pyogenes is one of the major human pathogens. It has two CRISPR loci, including CRISPR01 and CRISPR02. The first aim of this study was to analyze the distribution of CRISPR-associated genes cassette (cas) and CRISPR arrays in highly prevalent emm types. Since antibiotic-resistant genes are frequently encoded in foreign nucleic acids, the second aim was to analyze whether erythromycin susceptibility is associated with characteristics of CRISPR elements. In the first part, the cas cassette and CRISPR array in two CRISPR loci were analyzed in a total of 332 strains, including emm1, emm3, emm4, emm12, and emm28 strains. All strains had at least one cas cassette or CRISPR array. More than 90% of the spacers were found in one emm type, specifically. Comparing the consistency between emm and CRISPR types by Simpson’s index of diversity and adjusted Wallace coefficient, CRISPR01 type was correlated with the emm type of S. pyogenes, and CRISPR02 showed unidirectional congruence to emm type, suggesting CRISPR typing can be used as an alternative way to analyze the emm type of S. pyogenes. In the second part, erythromycin susceptibility of 330 isolates collected during 1997-2003 was analyzed. Among 29 emm types, emm12, emm75, and emm92 showed significant changes in erythromycin-resistance rates. By analyzing the spacers from two CRISPR loci, I found that spacer contents in emm12, emm75, and emm92 strains were associated with erythromycin susceptibility. The strains with fewer spacers were more resistant to erythromycin. Moreover, in emm4 strains, shown no significant change in their annual erythromycin-resistance rate, CRISPR type and number of spacers were not associated with erythromycin susceptibility. These results highlight a novel association between CRISPR spacer content and erythromycin susceptibility in S. pyogenes. Together, these evidences indicate that CRISPR is a good marker for molecular epidemiology in S. pyogenes.
論文目次 1 中文摘要 i
2 Abstract iii
3 Acknowledgement v
4 Table of Contents vi
5 List of Tables viii
6 List of Figures ix
7 Abbreviations x
8 Introduction 1
8.1 General characterization of S. pyogenes 1
8.2 Antibiotic susceptibility of S. pyogenes 1
8.3 S. pyogenes typing 3
8.3.1 emm type 4
8.3.2 emm-cluster type 4
8.3.3 Polymorphism of sic 5
8.3.4 Direct repeats 6
8.4 Introduction of CRISPR 6
8.5 Classification of CRISPR 8
8.5.1 CRISPR type I 8
8.5.1.1 Immunization of CRISPR type I 8
8.5.1.2 Immunity of CRISPR type I 9
8.5.2 CRISPR type II 10
8.5.2.1 Immunization of CRISPR type II 10
8.5.2.2 Immunity of CRISPR type II 10
8.5.3 CRISPR type III 11
8.5.4 Novel type of CRISPR 12
8.6 Application of CRISPR 12
8.6.1 Application on genome-editing 12
8.6.2 Application on gene regulation 13
8.6.3 Application on molecular typing 13
8.6.3.1 Association to antibiotic resistance 15
8.7 The aims of this study 16
9 Materials and Methods 18
9.1 Bacterial collection 18
9.2 Pulsed-field gel electrophoresis (PFGE) 18
9.3 Antibiotic susceptibility tests 19
9.4 Determination of emm type 20
9.5 Detection of the CRISPR and cas genes 21
9.5.1 Detection through experiments 21
9.5.2 Detection through in silico analysis 22
9.6 Identification of the proto-spacer location 24
9.7 Estimation of diversity index and grouping comparison coefficients 24
9.8 Statistical analysis 25
10 Results 27
10.1 Part I. Clustered regularly interspaced short palindromic repeats are emm type-specific in highly prevalent S. pyogenes 27
10.1.1 Presence of CRISPR in S. pyogenes 27
10.1.2 Analysis of the spacer contents in CRISPR01 and CRISPR02 loci 28
10.1.3 Association between emm and CRISPR 29
10.2 Arrangement and number of CRISPR spacers are associated with EM susceptibility in emm12, emm75, and emm92 of S. pyogenes 31
10.2.1 Analysis of the emm types and changes of EM susceptibility 31
10.2.2 Association of spacer contents and EM susceptibility in changing populations 32
10.2.3 Fewer spacers in EM-resistant strains 33
10.2.4 No association between CRISPR and EM susceptibility in stable populations 34
10.2.5 The presence of cas genes in emm4, emm12, emm75, and emm92 strains 35
10.2.6 Proto-spacers in emm4, emm12, emm75, and emm92 strains 36
11 Discussion 37
12 References 43
Tables 67
Figures 84
Appendix 1. The activity of CRISPR 90
Appendix 2. The immunity mechanism of CRISPR types I and II. 91
Appendix 3. Introduction of the tools to identify the CRISPR array 92
Appendix 4. Proto-spacers of emm4, emm12, emm75, and emm92 strains found in Genbank database 94
Appendix 5. Reagents 118
Appendix 6. Formulas 119
Appendix 7. Instruments 120

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