弗劳氏枸橼酸杆菌分子分型和毒力岛分析
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摘要
本文探索了弗劳氏枸橼酸杆菌作为肠道病原菌的可能性。根据我们实验室完成的弗劳氏枸橼酸杆菌CF72菌株的基因组序列和多位点序列分析(MLST)基因选择的原则,我们选择了7个基因,建立了弗劳氏枸橼酸杆菌的MLST方法。根据该方法,可把36株菌分成12个序列型(ST型)。使用获得的7个管家基因序列的种系发生关系分析发现,弗劳氏枸橼酸杆菌可分为A、B两大类,A类仅包括ST9,含1株菌;B类包括其余的11个ST型。B类又可以聚为两类。B1类包括2个ST型2株菌:ST8、ST12。B2类包括9个ST型33株菌。其中ST1、ST3、ST4亲缘关系比较近,ST2、ST5亲缘关系比较近。这5个型别包括29株菌,属于优势ST型。从菌株的来源来看,有7个ST型仅包括人源菌株,1个ST型仅包括动物源菌株,4个ST型,如ST1、ST2、ST3、ST5,包括动物源和人源菌株。
根据我们实验室完成的基因组分析,我们发现弗劳氏枸橼酸杆菌CF72菌株有49个基因组岛。根据功能分为10类:其中代谢岛17个,转运岛7个,噬菌体相关岛7个,DNA/RNA组装岛5个,细胞结构岛3个,DNA重组岛1个,功能不明的1个,其他1个,耐药性岛1个,毒力岛6个。在检测的36株菌中,只有6株菌所有检测的49个基因岛全部阳性,都属于ST2型。噬菌体转导可能是病原菌致病性进化的重要机理之一。ST1、ST2、ST3、ST4序列型的弗劳氏枸橼酸杆菌的噬菌体相关岛的分布,也和其他ST型有明显差异。GI22噬菌体相关岛可能和生物膜形成有关,在36株菌株中19株检测阳性,包括ST1(7/13株)、ST2(7/7株)、ST3(3/4株)、ST4(1/3株)、ST8(1/1株)。在36株菌中,有6株菌的GI13、GI29、GI30检测为阳性,这6株菌属于ST2型。GI36有7株菌检测阳性,包括ST2型6株菌和ST1型1株菌。噬菌体岛的分布提示,ST1、ST2、ST3、ST4、ST8的噬菌体转导比较活跃,其中ST1、ST3、ST4等以GI22为主,ST2也以其他几个噬菌体岛为主。噬菌体岛的分布具有ST型分布特征,主要分布在上述可能和致病性相关的ST型中。在6个毒力岛中,在36株菌中都能检测到的毒力岛有3个:包括编码铁转运系统的GI5、编码Tol-Pal内膜蛋白GI7、编码Curli菌毛蛋白GI9。编码侵袭相关菌毛蛋白GI6岛,可以在35株菌中都检测到。唯一没有完整检测到GI6毒力岛的菌株是CF5,属于ST9。编码O抗原的毒力岛GI24,在29株菌能够检测到。具有GI24岛的菌株分别是为ST1、ST2、ST3、ST4、ST5。这些ST型均属于优势ST型。编码亚碲酸钾抗性GI44岛,能够在8株菌中检测到,其中有6株菌属于ST2,其余两株分别属于ST6和ST7。
Hela细胞粘附实验发现,36株菌中有34株具有甘露糖抗性粘附,其中粘附力强的菌株3株,分别属于ST1、ST3、ST12;中等粘附18株,16株属于ST1、ST2、ST3、ST5。结果提示,以ST9为代表的A类可能是致病性最弱的,它不具有粘附力,毒力岛(GI6、GI24、GI44)检测也为阴性。Hela细胞细胞毒性试验发现,在36株菌中,CF74在作用10小时,具有较强的细胞毒性作用。除了细胞毒性作用外,CF74菌株的粘附力也比较强,属于ST12型。
简言之,我们发展了一种弗劳氏枸橼酸杆菌的MLST分析方法。使用这种方法,可将36株菌分为12个ST型。其中ST1、ST2、ST3、ST4、ST5属于优势型。这些ST型弗劳氏枸橼酸杆菌在基因组岛分布、毒力岛分布、噬菌体岛分布等方面,和其他ST型菌株相比,有明显差异。
病原性细菌的一个最基本的特征就是入侵宿主,并在宿主体内找到适合自己生存的小环境。经典的EPEC(Enteropathogenic Escherichia coli肠致病性大肠杆菌)和EHEC(Enterohemorrhagic Escherichia coli肠出血性大肠杆菌)入侵宿主的第一步是在感染粘膜细胞表面形成一种经典的病理损伤过程,称为粘附抹平效应(Attaching and Effacing lesions A/E)。该损伤在其致病过程中起了关键作用。其特点是:细菌紧密粘附粘膜表面,感染细胞微绒毛的丢失,细菌粘附处形成一个致密的肌动蛋白垫。
已有的研究的发现:该效应是由LEE(Locus of enterocyte effacement)毒力岛所编码的三型分泌系统(TypeⅢsecretion systerm TTSS)产生的。尽管EPEC和EHEC都具有LEE系统,但是它们的作用机制却有很大的差别,分别是通过Nck或TccP(Tir cytoskeleton coupling protein)蛋白两种不同的途径来激活细胞N-WASP蛋白,从而引起细胞肌动蛋白的聚集。因此,多年来,在体外细胞培养感染模型中,使用荧光染料标记细胞肌动蛋白聚集(Fluorescent actin stainingFAS),一直作为研究A/E损伤的模型和判断EPEC和EHEC菌株是否具有致病力的标准。
在本研究中,我们发现了一大类具有代表性的EPEC O125:H6菌株,这类菌株既不能利用Nck途径也不能利用TccP途径,根据前述的研究结论,这类菌株将不能引起肌动蛋白的聚集,因此在活体外器官组织培养感染模型中也不能引起A/E损伤。但本研究发现:该类菌株在体外细胞培养感染模型中能引起微弱的肌动蛋白的聚集,而且,在体外人肠器官组织培养感染模型中,EPEC O125:H6还能够造成经典的A/E损伤。是否存在其他途径引起A/E损伤还是A/E损伤不需要肌动蛋白的聚集?进一步的研究发现:EPEC O125:H6表达外源TccP后,可以在体外的细胞模型上引起有效的肌动蛋白聚集,在体外人肠器官组织感染模型中粘附能力也明显增强,在细菌粘附处还能够检测到N-WASP蛋白。
上述研究结果显示:在自然界里存在着一类不依赖于Nck或TccP途径来粘附肠道上皮产生A/E损伤的大肠杆;在体外细胞培养感染模型上引起肌动蛋白聚集现象,不应看作是EPEC和EHEC毒力的标志。
In this study, we explored the potential of Citrobacter freundii as a cause of infection diarrhea. Using the sequence information of CF72 complete genome sequence and following the principles on designing of the MLST, we developed a MLST scheme for Citrobacter freundii by choosing 7 house keeping genes. A total of 12 different STs were assigned in the 36 isolates. Phylogenetic tree based on the concatenated nucleotide sequences of the seven genes showed that the 36 isolates could be divided into 2 Clusters, namely CluterA and ClusterB. The ClusterA contained ST9, only one isolated from human in this Cluster. Cluster B contained the rest of the 11 STs, which could be subdivided into B1 and B2. B1 contained two STs , 2 isolates in B1, namely ST8 and ST12. B2 contained 9 STs of 33 isolates. ST1, ST3 and ST4 as well as ST2 and ST5 were closely related. The 4 STs contained 26 isolates and belonged to the common STs. From the original source of the strains, seven STs only contained the isolates from humans, one ST only contained the isolate from animals, four STs (ST1, ST2, ST3, ST5) contained the isolates from both humans and animals.
Based on the complete genome sequence, we found 49 genomic islands(GI). It could be divided into 10 categories: 17 GIs related to metabolism, 7 GIs encoding transport proteins, 7 GIs related to phage related genes, 5 GIs related to DNA/RNA processing gene, 3 GIs encoding cell structure proteins, 1 GI encoding DNA recombination, 1 GI related to function unknown, 1 GI encoding antibiotic resistance, 6 GIs ecoding virulence related proteins . Screening the 49 GIs in the 36 isolates, only 6 ST2 isolates contained all the GIs. Phages took important function in the evolution of the bacteria. The distribution of the phage related GIs in ST1, ST2, ST3, ST4 isolates were distinctly different from other STs. Phage related GI22 encoded the protein which was related to the biofilm. The STs that having GI22 (19 isolates) included ST1(7/13), ST2(7/7), ST3(3/4), ST4(l/3), ST8(1/1). Only 6 ST2 isolates had the phage related GIB, GI29, GI30. Phage related GI36 could be detected in 7 isolates, in which six belonged to ST2 and one belonged to ST1. The observation about distribution of phage related GIs suggested that the isolates of ST1, ST2, ST3, ST4 were relatively more active in horizontal gene transfer by phage. ST1, ST3, ST4 were more related to G122, while ST2 more related to others GIs. The distribution of phage related GIs was closely related to STs, in which existed in the possible virulence related islands. Three virulence related GIs could be detected in all isolates, and they were GI5 encoding OmpX-SfaABC ABC-transporter, GI7 encoding Tol-PaL inner member protein, GI9 encoding Curli pilus. One virulence related GI encoding invasion related Fim proteins could be detected in isolates except strain CF5(ST9). One virulence related GI encoding O-antigen could be detected in 29 isolates. The isolates belonged to the common STs. One virulence related GI encoding the tellurite resistance could be detected in 8 strains, in which six existing in ST2, one in ST6 and one in ST7.
The observation about the adhesive properties of Citrobacter freundii showed that 34 isolates could adhere to Hela cell. Adhesion index indicated that 3 isolates had the strong adhesive ability, which belonged to ST1, ST3, ST12. Eighteen isolates had middle adhesive ability, in which 16 isolates belonged to ST1, ST3, ST2, ST5. The representative ST9 from ClusterA was relatively less pathogenic strain for the reason that the Virulence related GIs (GI6、GI24、GI44) were not detected in ST9 and no adhesive ability was observed. The results of the cytotoxicy of Hela cell showed that the CF74 (ST12) induced significantly different level after 10 hours incubation than others, and it also had strong adhesive ability to Hela cell.
In summery, we developed a MLST method for Citrobacter freundii. 12 different STs were assigned to 36 isolates. 5 STs (ST1, ST2, ST3, ST4, ST5) were the common STs which were distinctly different from others on the aspects of distribution of GIs especially virulence related islands, phage related islands.
Other project during PHD:
We report that EPEC O125:H6, which represent a large category of strains, lack the ability to utilize either Nck or TccP and hence trigger actin polymerization in vitro only inefficiently. These results show the existence of a natural category of EPEC that colonizes the gut mucosa using Nck and TccP independent mechanisms. Importantly, the results highlight yet again the fact that conclusions made on the basis of in vitro cell culture models cannot be extrapolated wholesale to infection of mucosal surfaces and that the ability to induce actin polymerization on cultured cells should not be used as a definitive marker for EPEC and EHEC virulence.
Typical enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli colonize the gut epithelium via formation of a distinct histopathological lesion name attaching and effacing (A/E).A/E lesions are characterized by loss of microvilli, an intimate adherence of bacteria adjacent to the host cell membrance and the generation of organized cytoskeletal structures containing filamentous actin beneath sites of bacterial attachment,termed actin polymerization.
The gene necessary for A/E lesion formation in vitro are carried on the locus of enterocyte effacement, which encodes a type III secretion systerm. Although EPEC and EHEC prodece highly similar lesions by LEE, the mechanisms are different. The actin polymerization induced by EPEC is in a Nck-dependent pathway while EHEC in a TccP-dependent pathway to activate N-WASP and to trigger actin polymerization in cultured cells. This phenotype is used as a marker for the pathogenic potential of EPEC and EHEC strains.
In this paper we report that EPEC O125:H6, which represent a large category of strains, lack the ability to utilize either Nck or TccP and hence trigger actin polymerization in vitro only inefficiently. However, we show that infection of human intestinal biopsies with EPEC O125:H6 results in formation of typical attaching and effacing lesions. Expressing TccP in EPEC O125:H6, which harbor an EHEC O157-like Tir, resulted in efficient actin polymerization in vitro and enhanced colonization of human intestinal in vitro organ cultures with detectable N-WASP and electron dense material at the site of bacterial adhesion. These results show the existence of a natural category of EPEC that colonizes the gut mucosa using Nck and TccP independent mechanisms. Importantly, the results highlight yet again the fact that conclusions made on the basis of in vitro cell culture models cannot be extrapolated wholesale to infection of mucosal surfaces and that the ability to induce actin polymerization on cultured cells should not be used as a definitive marker for EPEC and EHEC virulence.
根据我们实验室完成的基因组分析,我们发现弗劳氏枸橼酸杆菌CF72菌株有49个基因组岛。根据功能分为10类:其中代谢岛17个,转运岛7个,噬菌体相关岛7个,DNA/RNA组装岛5个,细胞结构岛3个,DNA重组岛1个,功能不明的1个,其他1个,耐药性岛1个,毒力岛6个。在检测的36株菌中,只有6株菌所有检测的49个基因岛全部阳性,都属于ST2型。噬菌体转导可能是病原菌致病性进化的重要机理之一。ST1、ST2、ST3、ST4序列型的弗劳氏枸橼酸杆菌的噬菌体相关岛的分布,也和其他ST型有明显差异。GI22噬菌体相关岛可能和生物膜形成有关,在36株菌株中19株检测阳性,包括ST1(7/13株)、ST2(7/7株)、ST3(3/4株)、ST4(1/3株)、ST8(1/1株)。在36株菌中,有6株菌的GI13、GI29、GI30检测为阳性,这6株菌属于ST2型。GI36有7株菌检测阳性,包括ST2型6株菌和ST1型1株菌。噬菌体岛的分布提示,ST1、ST2、ST3、ST4、ST8的噬菌体转导比较活跃,其中ST1、ST3、ST4等以GI22为主,ST2也以其他几个噬菌体岛为主。噬菌体岛的分布具有ST型分布特征,主要分布在上述可能和致病性相关的ST型中。在6个毒力岛中,在36株菌中都能检测到的毒力岛有3个:包括编码铁转运系统的GI5、编码Tol-Pal内膜蛋白GI7、编码Curli菌毛蛋白GI9。编码侵袭相关菌毛蛋白GI6岛,可以在35株菌中都检测到。唯一没有完整检测到GI6毒力岛的菌株是CF5,属于ST9。编码O抗原的毒力岛GI24,在29株菌能够检测到。具有GI24岛的菌株分别是为ST1、ST2、ST3、ST4、ST5。这些ST型均属于优势ST型。编码亚碲酸钾抗性GI44岛,能够在8株菌中检测到,其中有6株菌属于ST2,其余两株分别属于ST6和ST7。
Hela细胞粘附实验发现,36株菌中有34株具有甘露糖抗性粘附,其中粘附力强的菌株3株,分别属于ST1、ST3、ST12;中等粘附18株,16株属于ST1、ST2、ST3、ST5。结果提示,以ST9为代表的A类可能是致病性最弱的,它不具有粘附力,毒力岛(GI6、GI24、GI44)检测也为阴性。Hela细胞细胞毒性试验发现,在36株菌中,CF74在作用10小时,具有较强的细胞毒性作用。除了细胞毒性作用外,CF74菌株的粘附力也比较强,属于ST12型。
简言之,我们发展了一种弗劳氏枸橼酸杆菌的MLST分析方法。使用这种方法,可将36株菌分为12个ST型。其中ST1、ST2、ST3、ST4、ST5属于优势型。这些ST型弗劳氏枸橼酸杆菌在基因组岛分布、毒力岛分布、噬菌体岛分布等方面,和其他ST型菌株相比,有明显差异。
病原性细菌的一个最基本的特征就是入侵宿主,并在宿主体内找到适合自己生存的小环境。经典的EPEC(Enteropathogenic Escherichia coli肠致病性大肠杆菌)和EHEC(Enterohemorrhagic Escherichia coli肠出血性大肠杆菌)入侵宿主的第一步是在感染粘膜细胞表面形成一种经典的病理损伤过程,称为粘附抹平效应(Attaching and Effacing lesions A/E)。该损伤在其致病过程中起了关键作用。其特点是:细菌紧密粘附粘膜表面,感染细胞微绒毛的丢失,细菌粘附处形成一个致密的肌动蛋白垫。
已有的研究的发现:该效应是由LEE(Locus of enterocyte effacement)毒力岛所编码的三型分泌系统(TypeⅢsecretion systerm TTSS)产生的。尽管EPEC和EHEC都具有LEE系统,但是它们的作用机制却有很大的差别,分别是通过Nck或TccP(Tir cytoskeleton coupling protein)蛋白两种不同的途径来激活细胞N-WASP蛋白,从而引起细胞肌动蛋白的聚集。因此,多年来,在体外细胞培养感染模型中,使用荧光染料标记细胞肌动蛋白聚集(Fluorescent actin stainingFAS),一直作为研究A/E损伤的模型和判断EPEC和EHEC菌株是否具有致病力的标准。
在本研究中,我们发现了一大类具有代表性的EPEC O125:H6菌株,这类菌株既不能利用Nck途径也不能利用TccP途径,根据前述的研究结论,这类菌株将不能引起肌动蛋白的聚集,因此在活体外器官组织培养感染模型中也不能引起A/E损伤。但本研究发现:该类菌株在体外细胞培养感染模型中能引起微弱的肌动蛋白的聚集,而且,在体外人肠器官组织培养感染模型中,EPEC O125:H6还能够造成经典的A/E损伤。是否存在其他途径引起A/E损伤还是A/E损伤不需要肌动蛋白的聚集?进一步的研究发现:EPEC O125:H6表达外源TccP后,可以在体外的细胞模型上引起有效的肌动蛋白聚集,在体外人肠器官组织感染模型中粘附能力也明显增强,在细菌粘附处还能够检测到N-WASP蛋白。
上述研究结果显示:在自然界里存在着一类不依赖于Nck或TccP途径来粘附肠道上皮产生A/E损伤的大肠杆;在体外细胞培养感染模型上引起肌动蛋白聚集现象,不应看作是EPEC和EHEC毒力的标志。
In this study, we explored the potential of Citrobacter freundii as a cause of infection diarrhea. Using the sequence information of CF72 complete genome sequence and following the principles on designing of the MLST, we developed a MLST scheme for Citrobacter freundii by choosing 7 house keeping genes. A total of 12 different STs were assigned in the 36 isolates. Phylogenetic tree based on the concatenated nucleotide sequences of the seven genes showed that the 36 isolates could be divided into 2 Clusters, namely CluterA and ClusterB. The ClusterA contained ST9, only one isolated from human in this Cluster. Cluster B contained the rest of the 11 STs, which could be subdivided into B1 and B2. B1 contained two STs , 2 isolates in B1, namely ST8 and ST12. B2 contained 9 STs of 33 isolates. ST1, ST3 and ST4 as well as ST2 and ST5 were closely related. The 4 STs contained 26 isolates and belonged to the common STs. From the original source of the strains, seven STs only contained the isolates from humans, one ST only contained the isolate from animals, four STs (ST1, ST2, ST3, ST5) contained the isolates from both humans and animals.
Based on the complete genome sequence, we found 49 genomic islands(GI). It could be divided into 10 categories: 17 GIs related to metabolism, 7 GIs encoding transport proteins, 7 GIs related to phage related genes, 5 GIs related to DNA/RNA processing gene, 3 GIs encoding cell structure proteins, 1 GI encoding DNA recombination, 1 GI related to function unknown, 1 GI encoding antibiotic resistance, 6 GIs ecoding virulence related proteins . Screening the 49 GIs in the 36 isolates, only 6 ST2 isolates contained all the GIs. Phages took important function in the evolution of the bacteria. The distribution of the phage related GIs in ST1, ST2, ST3, ST4 isolates were distinctly different from other STs. Phage related GI22 encoded the protein which was related to the biofilm. The STs that having GI22 (19 isolates) included ST1(7/13), ST2(7/7), ST3(3/4), ST4(l/3), ST8(1/1). Only 6 ST2 isolates had the phage related GIB, GI29, GI30. Phage related GI36 could be detected in 7 isolates, in which six belonged to ST2 and one belonged to ST1. The observation about distribution of phage related GIs suggested that the isolates of ST1, ST2, ST3, ST4 were relatively more active in horizontal gene transfer by phage. ST1, ST3, ST4 were more related to G122, while ST2 more related to others GIs. The distribution of phage related GIs was closely related to STs, in which existed in the possible virulence related islands. Three virulence related GIs could be detected in all isolates, and they were GI5 encoding OmpX-SfaABC ABC-transporter, GI7 encoding Tol-PaL inner member protein, GI9 encoding Curli pilus. One virulence related GI encoding invasion related Fim proteins could be detected in isolates except strain CF5(ST9). One virulence related GI encoding O-antigen could be detected in 29 isolates. The isolates belonged to the common STs. One virulence related GI encoding the tellurite resistance could be detected in 8 strains, in which six existing in ST2, one in ST6 and one in ST7.
The observation about the adhesive properties of Citrobacter freundii showed that 34 isolates could adhere to Hela cell. Adhesion index indicated that 3 isolates had the strong adhesive ability, which belonged to ST1, ST3, ST12. Eighteen isolates had middle adhesive ability, in which 16 isolates belonged to ST1, ST3, ST2, ST5. The representative ST9 from ClusterA was relatively less pathogenic strain for the reason that the Virulence related GIs (GI6、GI24、GI44) were not detected in ST9 and no adhesive ability was observed. The results of the cytotoxicy of Hela cell showed that the CF74 (ST12) induced significantly different level after 10 hours incubation than others, and it also had strong adhesive ability to Hela cell.
In summery, we developed a MLST method for Citrobacter freundii. 12 different STs were assigned to 36 isolates. 5 STs (ST1, ST2, ST3, ST4, ST5) were the common STs which were distinctly different from others on the aspects of distribution of GIs especially virulence related islands, phage related islands.
Other project during PHD:
We report that EPEC O125:H6, which represent a large category of strains, lack the ability to utilize either Nck or TccP and hence trigger actin polymerization in vitro only inefficiently. These results show the existence of a natural category of EPEC that colonizes the gut mucosa using Nck and TccP independent mechanisms. Importantly, the results highlight yet again the fact that conclusions made on the basis of in vitro cell culture models cannot be extrapolated wholesale to infection of mucosal surfaces and that the ability to induce actin polymerization on cultured cells should not be used as a definitive marker for EPEC and EHEC virulence.
Typical enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli colonize the gut epithelium via formation of a distinct histopathological lesion name attaching and effacing (A/E).A/E lesions are characterized by loss of microvilli, an intimate adherence of bacteria adjacent to the host cell membrance and the generation of organized cytoskeletal structures containing filamentous actin beneath sites of bacterial attachment,termed actin polymerization.
The gene necessary for A/E lesion formation in vitro are carried on the locus of enterocyte effacement, which encodes a type III secretion systerm. Although EPEC and EHEC prodece highly similar lesions by LEE, the mechanisms are different. The actin polymerization induced by EPEC is in a Nck-dependent pathway while EHEC in a TccP-dependent pathway to activate N-WASP and to trigger actin polymerization in cultured cells. This phenotype is used as a marker for the pathogenic potential of EPEC and EHEC strains.
In this paper we report that EPEC O125:H6, which represent a large category of strains, lack the ability to utilize either Nck or TccP and hence trigger actin polymerization in vitro only inefficiently. However, we show that infection of human intestinal biopsies with EPEC O125:H6 results in formation of typical attaching and effacing lesions. Expressing TccP in EPEC O125:H6, which harbor an EHEC O157-like Tir, resulted in efficient actin polymerization in vitro and enhanced colonization of human intestinal in vitro organ cultures with detectable N-WASP and electron dense material at the site of bacterial adhesion. These results show the existence of a natural category of EPEC that colonizes the gut mucosa using Nck and TccP independent mechanisms. Importantly, the results highlight yet again the fact that conclusions made on the basis of in vitro cell culture models cannot be extrapolated wholesale to infection of mucosal surfaces and that the ability to induce actin polymerization on cultured cells should not be used as a definitive marker for EPEC and EHEC virulence.
引文
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