O1群El Tor型霍乱弧菌分型噬菌体VP5和其受体的研究
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摘要
霍乱弧菌(Vibrio cholerae)是急性致死性腹泻病——霍乱的致病菌。霍乱弧菌已发现200多种不同的O抗原血清群,其中仅01群和0139群能够引起霍乱流行。目前处于霍乱的第七次世界范围的大流行中,与第六次大流行由古典生物型霍乱弧菌引起不同,第七次大流行的致病菌株是El Tor型霍乱弧菌。目前在我国使用的分型方法是噬菌体-生物分型,可将各种来源的01群El Tor型霍乱弧菌分为32个噬菌体型和12个生物型,结合二者又将菌株分为流行株和非流行株,可作为追溯传染来源、传播途径和分析流行形式的流行病学工具之一。在实际中应用噬菌体-生物分型的结果区别应对流行株和非流行株,对于霍乱的预防控制起到了事半功倍的效果。
VP5是五个分型噬菌体之一,了解分型噬菌体的形态结构、基因组特征,噬菌体感染霍乱弧菌的机制、噬菌体敏感菌株和抗性菌株之间的差异,对于认识噬菌体-生物型别指导霍乱防治的机理、了解01群El Tor型霍乱弧菌的遗传差异和分化有重要作用。基于噬菌体-生物分型的所有流行株型别中,仅有6b型霍乱弧菌对VP5噬菌体不敏感。1998至2001年,在我国四川省出现噬菌体—生物分型为6b的流行优势菌型,区别于同时期其他省份或四川省1998年前和2001年后的流行优势菌型(1b型)。我们试图从这一特殊菌型流行的现象出发,了解对VP5噬菌体不敏感的6b型菌株能够得以流行的机制,了解分型噬菌体VP5裂解霍乱弧菌的过程。
我们通过电镜观察到分型噬菌体VP5头部呈正六边形,边长约37nm,半径约31nm,具有短尾,尾长约18nm,推测其为典型的短尾20面体结构。其基因组测序得到长度为39789bps的序列,预测了36个ORF和其中7个ORF的功能,前16个在正链上,后20个在负链上。该基因组未发现rRNA和tRNA基因。
我们选择了1998至2001年四川省流行的01群霍乱弧菌6b菌株22株和同时期四川及其他省份流行的霍乱弧菌1b菌株23株。实验证实了1998—2001年期间在四川流行的1b型和6b型菌株均为产毒株。通过对这45株霍乱弧菌的ompW基因与N16961序列比对发现6b菌株的ompW基因ORF第298-308碱基位置缺失了11个bp,而其余23株菌非6b型菌株的ompW基因ORF是完整的。在1b和6b菌型复杂的遗传背景下,这一特征可能可以作为追踪这类具有特殊遗传背景的菌型的遗传标记。N16961-dompW在低营养状态下的生长优势和更强的生物膜形成能力,提示这一菌型在环境适应中的优势。
将N16961的ompW基因以氯霉素基因替代后,N16961由VP5敏感变为VP5抗性,回补ompW基因,缺失株能恢复对VP5的敏感。表达纯化的OmpW蛋白可以使VP5噬菌体对N16961的裂解钝化,说明N16961中OmpW蛋白为霍乱弧菌分型噬菌体VP5的受体。
通过本研究,我们对01群El Tor型霍乱弧菌分型噬菌体VP5的形态结构、基因组及其受体,6b型菌株的遗传特征和分子标记,都有了初步的认识,能够帮助我们理解噬菌体-生物分型的理论基础和噬菌体对于菌株环境适应的意义。
模式生物是研究病原细菌的重要工具,常利用模式生物模拟感染或共生的过程,来研究病原细菌的毒力因子、致病机制、与宿主相互作用、生物膜形成、耐药等各个方面。目前常用于研究霍乱弧菌的有小鼠、大鼠、兔等动物,都由于操作较为复杂,价格相对昂贵,影响结果的因素多而受到局限。秀丽隐杆线虫是一种广泛应用的模式生物,便于喂养和观察,从1999年开始用于致病菌的研究。目前已在多种病原菌的研究中得到应用。
这里我们尝试将秀丽隐杆线虫应用于霍乱弧菌的研究,实验中我们首先确定秀丽隐杆线虫可以霍乱弧菌为食,与大肠杆菌OP50对比,在霍乱弧菌N16961的菌苔上秀丽隐杆线虫生长和发育进程没有明显改变。我们选择了来源于01和0139群不同血清型CT阳性或阴性的霍乱弧菌共24株,通过PCR验证这些菌株都存在文献报道的霍乱弧菌对秀丽隐杆线虫致死必须的prtV基因。以大肠杆菌OP50为对照,检测秀丽隐杆线虫在24株霍乱弧菌菌苔上的生存时间,做出生存曲线,分组比较。结果显示,实验中使用霍乱弧菌较之大肠杆菌对照,使秀丽隐杆线虫生存时间明显缩短,有致死性作用。实验中使用01群和0139群霍乱弧菌较之大肠杆菌对照都有致死性作用,但两群之间无明显差异。在本实验中,CT阳性和CT阴性的霍乱弧菌较之大肠杆菌对照都有致死性作用,两者比较CT阳性组能将线虫更快致死。
本研究是将秀丽隐杆线虫应用于霍乱弧菌研究的初步尝试。参考利用秀丽隐杆线虫研究其他病原细菌的方法,初步建立了使用秀丽隐杆线虫研究霍乱弧菌的实验方法。然而,将秀丽隐杆线虫作为霍乱弧菌的研究模型,尚有理论基础需要完善、实验细节需要摸索,这些都有待于进一步的工作去探索。
National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention.
State Key Laboratory for Infectious Disease Prevention and Control (China CDC).
Cholerae is an acute lethal diarrhea caused by Vibrio cholerae. It has been found more than 200 kinds of different O antigen serogroups Vibrio cholerae, of which only-O1 and O139 serogroups can cause cholera epidemics. Seven cholera pandemics have occurred in history. It is still in the seventh pandemic caused by Vibrio cholerae El Tor biotype. Vibrio cholerae phagetyping is commonly used typing method. In china,O1 El Tor Vibrio cholerae is divided into 32 phagetypes and 12 biotypes by Vibrio cholerae phagetyping combined with the biological classification. These can be used as tools for trace infection sources, transmission and analysis of popular forms of epidemiological.
To understand the mechanism of phage-biotype guide to cholera prevention and control, to understand the O1 El Tor Vibrio cholerae genetic diversity and differentiation, it is important to explore the morphology, genome features, the mechanism of Vibrio cholerae phage infection and the differences between the phage-sensitive strains and resistant strains.
In all phage-biotypes those can cause cholera epidemics, only 6b is not sensitive to the phage VP5. Between 1998 to 2001, cholera epidemic caused by 6b phage-biotype Vibrio cholerae in Sichuan Province, while dominant type of epidemic strains in other provinces in the same period and that in Sichuan Province before 1998 and after 2001 are all 1b strains. We try starting from this phenomenon, to understand prevalent mechanism of 6b which insensitive to VP5 phage, to understand the process of Vibrio cholerae VP5 lysis. All prevailing strains in Sichuan Province from 1998 to 2001 determined as 1b and 6b by phage-biotyping were toxigenic. A total of 24 patterns were obtained in PFGE analysis, in which one predominant pattern consisted of 13 strains. Parts of 1b and 6b strains from Sichuan and parts of the lb strains from other provinces showed the same PFGE pattern. Mutation 11bp in ompW gene was found in 6b strains. Vibrio cholerae 01 6b strains in Sichuan Province from 1998 to 2001 have special genetic markers, and may evolutionary correlated with contemporaneous 1b strains.
Phage VP5 observed with electron microscopy have hexagonal head and short-tailed. Therefore, we speculated that VP5 is icosahedron. We sequenced the whole genome of VP5 and get a sequence of length 39789bps, predicted 36 ORF of which 16 are in positive chain and 20 are in negtive chain. The average length of VP5 ORF is 941bp, the longest gene is 2349bp. In this genome rRNA and tRNA gene was not found. We confirmed OmpW protein in N16961 is the receptor of phage VP5, for the ompW deletion mutant in N16961 get resistant to VP5 and the complemeted mutant strain is sensitive to VP5. Expressed OmpW protein can neutralize Vibrio cholerae N16961 VP5 lysis, that supports the view.
Initially, we knew morphology, genome and receptor of 01 El Tor Vibrio cholerae typingphage VP5, and we found the tracking markers of 6b strains.
There is a continuing need for the development of simple animal models for the study of host-pathogen interactions. In the study of pathogenic bacteria, the appropriate model organism is very important for the experimental reliability, ease of use and analysis of experimental results. In order to understand the pathogenesis of bacterial pathogens or environmental survival related information, we need to simulate the case of infection or symbiosis during the process of interaction between pathogenic bacteria and model organisms. Currently, rabbits, mice, rats, etc. are used for Vibrio cholerae research. But those animal models have a variety of defects such as operate complexity, relatively expensive, and implementation difficulties to experiments e.g. large scale screening of strains. And because of the complexity of mammals, there are so many factors that could influence the results, which bring limitations to analysis of experimental results.
Caenorhabditis elegans feed on bacteria, so it is easy to feed in the laboratory. Caenorhabditis elegans became a new model organism as a facile and inexpensive host for human bacterial pathogens. Since 1999 it has been used in Pseudomonas aeruginosa, Enterococcus faecium, Staphylococcus aureus, Shigella flexneri, Pseudomonas aeruginosa, Yersinia, Listeria, Salmonella enterica, Burkholderia, Streptococcus pyogenes, Salmonella typhimurium, Bacillus thuringiensis, Serratia marcescens, Cryptococcus, Microbacterium nematophilum et al, to identify virulence factors, pathogenetic mechanism, host-pathogen interactions, biofilms, drug-resistance. As well as facilitating the identification and study of virulence mechanisms, simple model systems may also permit direct genetic approaches for the study of host defenses.
In this study, we first determine Caenorhabditis elegans can feed on Vibrio cholerae. Compared with those on E. coli OP50, Caenorhabditis elegans growth and development process did not change significantly on the Vibrio cholerae N16961. We have chosen 24 strains Vibrio cholerae 01 and 0139 serogroup, with CT positive or negative. These strains were verified by PCR the existence of prtV gene, which is considered needed for killing of Caenorhabditis elegans. E. coli OP50 as the control, we detect the ability of Vibrio cholerae 24 strains to kill Caenorhabditis elegans by making survival curves. The results showed that Vibrio cholerae used in experiments can make Caenorhabditis elegans survival time significantly shorter. Vibrio cholerae 01 serogroup were able to kill Caenorhabditis elegans worms as efficiently as Vibrio cholerae 0139 serogroup. But We found the CT-positive group killed worms more quickly than CT-negtive group.
This study is a initial attempt to use Caenorhabditis elegans on the study of Vibrio cholerae. The many experimental advantages associated with the use of the nematode Caenorhabditis elegans led us to investigate its interaction with Vibrio cholerae. Finally, we provide evidence that Caenorhabditis elegans may be a useful model host for Vibrio cholerae.
VP5是五个分型噬菌体之一,了解分型噬菌体的形态结构、基因组特征,噬菌体感染霍乱弧菌的机制、噬菌体敏感菌株和抗性菌株之间的差异,对于认识噬菌体-生物型别指导霍乱防治的机理、了解01群El Tor型霍乱弧菌的遗传差异和分化有重要作用。基于噬菌体-生物分型的所有流行株型别中,仅有6b型霍乱弧菌对VP5噬菌体不敏感。1998至2001年,在我国四川省出现噬菌体—生物分型为6b的流行优势菌型,区别于同时期其他省份或四川省1998年前和2001年后的流行优势菌型(1b型)。我们试图从这一特殊菌型流行的现象出发,了解对VP5噬菌体不敏感的6b型菌株能够得以流行的机制,了解分型噬菌体VP5裂解霍乱弧菌的过程。
我们通过电镜观察到分型噬菌体VP5头部呈正六边形,边长约37nm,半径约31nm,具有短尾,尾长约18nm,推测其为典型的短尾20面体结构。其基因组测序得到长度为39789bps的序列,预测了36个ORF和其中7个ORF的功能,前16个在正链上,后20个在负链上。该基因组未发现rRNA和tRNA基因。
我们选择了1998至2001年四川省流行的01群霍乱弧菌6b菌株22株和同时期四川及其他省份流行的霍乱弧菌1b菌株23株。实验证实了1998—2001年期间在四川流行的1b型和6b型菌株均为产毒株。通过对这45株霍乱弧菌的ompW基因与N16961序列比对发现6b菌株的ompW基因ORF第298-308碱基位置缺失了11个bp,而其余23株菌非6b型菌株的ompW基因ORF是完整的。在1b和6b菌型复杂的遗传背景下,这一特征可能可以作为追踪这类具有特殊遗传背景的菌型的遗传标记。N16961-dompW在低营养状态下的生长优势和更强的生物膜形成能力,提示这一菌型在环境适应中的优势。
将N16961的ompW基因以氯霉素基因替代后,N16961由VP5敏感变为VP5抗性,回补ompW基因,缺失株能恢复对VP5的敏感。表达纯化的OmpW蛋白可以使VP5噬菌体对N16961的裂解钝化,说明N16961中OmpW蛋白为霍乱弧菌分型噬菌体VP5的受体。
通过本研究,我们对01群El Tor型霍乱弧菌分型噬菌体VP5的形态结构、基因组及其受体,6b型菌株的遗传特征和分子标记,都有了初步的认识,能够帮助我们理解噬菌体-生物分型的理论基础和噬菌体对于菌株环境适应的意义。
模式生物是研究病原细菌的重要工具,常利用模式生物模拟感染或共生的过程,来研究病原细菌的毒力因子、致病机制、与宿主相互作用、生物膜形成、耐药等各个方面。目前常用于研究霍乱弧菌的有小鼠、大鼠、兔等动物,都由于操作较为复杂,价格相对昂贵,影响结果的因素多而受到局限。秀丽隐杆线虫是一种广泛应用的模式生物,便于喂养和观察,从1999年开始用于致病菌的研究。目前已在多种病原菌的研究中得到应用。
这里我们尝试将秀丽隐杆线虫应用于霍乱弧菌的研究,实验中我们首先确定秀丽隐杆线虫可以霍乱弧菌为食,与大肠杆菌OP50对比,在霍乱弧菌N16961的菌苔上秀丽隐杆线虫生长和发育进程没有明显改变。我们选择了来源于01和0139群不同血清型CT阳性或阴性的霍乱弧菌共24株,通过PCR验证这些菌株都存在文献报道的霍乱弧菌对秀丽隐杆线虫致死必须的prtV基因。以大肠杆菌OP50为对照,检测秀丽隐杆线虫在24株霍乱弧菌菌苔上的生存时间,做出生存曲线,分组比较。结果显示,实验中使用霍乱弧菌较之大肠杆菌对照,使秀丽隐杆线虫生存时间明显缩短,有致死性作用。实验中使用01群和0139群霍乱弧菌较之大肠杆菌对照都有致死性作用,但两群之间无明显差异。在本实验中,CT阳性和CT阴性的霍乱弧菌较之大肠杆菌对照都有致死性作用,两者比较CT阳性组能将线虫更快致死。
本研究是将秀丽隐杆线虫应用于霍乱弧菌研究的初步尝试。参考利用秀丽隐杆线虫研究其他病原细菌的方法,初步建立了使用秀丽隐杆线虫研究霍乱弧菌的实验方法。然而,将秀丽隐杆线虫作为霍乱弧菌的研究模型,尚有理论基础需要完善、实验细节需要摸索,这些都有待于进一步的工作去探索。
National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention.
State Key Laboratory for Infectious Disease Prevention and Control (China CDC).
Cholerae is an acute lethal diarrhea caused by Vibrio cholerae. It has been found more than 200 kinds of different O antigen serogroups Vibrio cholerae, of which only-O1 and O139 serogroups can cause cholera epidemics. Seven cholera pandemics have occurred in history. It is still in the seventh pandemic caused by Vibrio cholerae El Tor biotype. Vibrio cholerae phagetyping is commonly used typing method. In china,O1 El Tor Vibrio cholerae is divided into 32 phagetypes and 12 biotypes by Vibrio cholerae phagetyping combined with the biological classification. These can be used as tools for trace infection sources, transmission and analysis of popular forms of epidemiological.
To understand the mechanism of phage-biotype guide to cholera prevention and control, to understand the O1 El Tor Vibrio cholerae genetic diversity and differentiation, it is important to explore the morphology, genome features, the mechanism of Vibrio cholerae phage infection and the differences between the phage-sensitive strains and resistant strains.
In all phage-biotypes those can cause cholera epidemics, only 6b is not sensitive to the phage VP5. Between 1998 to 2001, cholera epidemic caused by 6b phage-biotype Vibrio cholerae in Sichuan Province, while dominant type of epidemic strains in other provinces in the same period and that in Sichuan Province before 1998 and after 2001 are all 1b strains. We try starting from this phenomenon, to understand prevalent mechanism of 6b which insensitive to VP5 phage, to understand the process of Vibrio cholerae VP5 lysis. All prevailing strains in Sichuan Province from 1998 to 2001 determined as 1b and 6b by phage-biotyping were toxigenic. A total of 24 patterns were obtained in PFGE analysis, in which one predominant pattern consisted of 13 strains. Parts of 1b and 6b strains from Sichuan and parts of the lb strains from other provinces showed the same PFGE pattern. Mutation 11bp in ompW gene was found in 6b strains. Vibrio cholerae 01 6b strains in Sichuan Province from 1998 to 2001 have special genetic markers, and may evolutionary correlated with contemporaneous 1b strains.
Phage VP5 observed with electron microscopy have hexagonal head and short-tailed. Therefore, we speculated that VP5 is icosahedron. We sequenced the whole genome of VP5 and get a sequence of length 39789bps, predicted 36 ORF of which 16 are in positive chain and 20 are in negtive chain. The average length of VP5 ORF is 941bp, the longest gene is 2349bp. In this genome rRNA and tRNA gene was not found. We confirmed OmpW protein in N16961 is the receptor of phage VP5, for the ompW deletion mutant in N16961 get resistant to VP5 and the complemeted mutant strain is sensitive to VP5. Expressed OmpW protein can neutralize Vibrio cholerae N16961 VP5 lysis, that supports the view.
Initially, we knew morphology, genome and receptor of 01 El Tor Vibrio cholerae typingphage VP5, and we found the tracking markers of 6b strains.
There is a continuing need for the development of simple animal models for the study of host-pathogen interactions. In the study of pathogenic bacteria, the appropriate model organism is very important for the experimental reliability, ease of use and analysis of experimental results. In order to understand the pathogenesis of bacterial pathogens or environmental survival related information, we need to simulate the case of infection or symbiosis during the process of interaction between pathogenic bacteria and model organisms. Currently, rabbits, mice, rats, etc. are used for Vibrio cholerae research. But those animal models have a variety of defects such as operate complexity, relatively expensive, and implementation difficulties to experiments e.g. large scale screening of strains. And because of the complexity of mammals, there are so many factors that could influence the results, which bring limitations to analysis of experimental results.
Caenorhabditis elegans feed on bacteria, so it is easy to feed in the laboratory. Caenorhabditis elegans became a new model organism as a facile and inexpensive host for human bacterial pathogens. Since 1999 it has been used in Pseudomonas aeruginosa, Enterococcus faecium, Staphylococcus aureus, Shigella flexneri, Pseudomonas aeruginosa, Yersinia, Listeria, Salmonella enterica, Burkholderia, Streptococcus pyogenes, Salmonella typhimurium, Bacillus thuringiensis, Serratia marcescens, Cryptococcus, Microbacterium nematophilum et al, to identify virulence factors, pathogenetic mechanism, host-pathogen interactions, biofilms, drug-resistance. As well as facilitating the identification and study of virulence mechanisms, simple model systems may also permit direct genetic approaches for the study of host defenses.
In this study, we first determine Caenorhabditis elegans can feed on Vibrio cholerae. Compared with those on E. coli OP50, Caenorhabditis elegans growth and development process did not change significantly on the Vibrio cholerae N16961. We have chosen 24 strains Vibrio cholerae 01 and 0139 serogroup, with CT positive or negative. These strains were verified by PCR the existence of prtV gene, which is considered needed for killing of Caenorhabditis elegans. E. coli OP50 as the control, we detect the ability of Vibrio cholerae 24 strains to kill Caenorhabditis elegans by making survival curves. The results showed that Vibrio cholerae used in experiments can make Caenorhabditis elegans survival time significantly shorter. Vibrio cholerae 01 serogroup were able to kill Caenorhabditis elegans worms as efficiently as Vibrio cholerae 0139 serogroup. But We found the CT-positive group killed worms more quickly than CT-negtive group.
This study is a initial attempt to use Caenorhabditis elegans on the study of Vibrio cholerae. The many experimental advantages associated with the use of the nematode Caenorhabditis elegans led us to investigate its interaction with Vibrio cholerae. Finally, we provide evidence that Caenorhabditis elegans may be a useful model host for Vibrio cholerae.
引文
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8.王汉章,黄玉英,张静,等.2001年全国霍乱疫情分析.中国预防医学杂志,2003,4(增刊)：13-15.
9.王汉章,黄玉英,张静,等.2002年全国霍乱疫情分析.中国预防医学杂志,2003,4(增刊)：9-12.
10. Guidolin,A., P.A. Manning.1987. Genetics of Vibrio cholerae and its bacteriophages. Microbiol. Rev.51:285-298
11. Kar,S.,R.K.Ghosh,and A.N.Ghosh.1996.integration of the DNA of a novel filamentous bacteriophage VSK from Vibrio cholerae 0139 into the host chromosomal DNA. FEMS Microbiol.Lett.145:17-22
12. Rowe, B., and J. A. Frost.1992. Vibrio phages and phage-typing, p.95-105. In D. Barua and W. B. Greenough, III (ed.), Cholera. Plenum Medical Book Co., New York.
13. Inoue T, Matsuzaki S and Tanaka S. A 26-kDa outer membrane protein, OmpK, common to Vibrio species is the receptor for a broad-host-range vibriophage, KVP40[J]. FEMS Microbiol Lett,1995,125:101-5
14. Prehm P, Jann B, Jann K, et al. On a bacteriophage T3 and T4 receptor region within the cell wall lipopolysaccharide of Escherichia coli B[J]. J Mol Biol, 1976,101:277-81
15. Merino S, Camprubi S and Tomas JM. Isolation and characterization of bacteriophage PM3 from Aeromonas hydrophila the bacterial receptor for which is the monopolar flagellum[J]. FEMS Microbiol Lett,1990,57:277-82
16.中华人民共和国卫生部疾病预防控制司.霍乱防治手册.第五版.1999.
17. Brussow H, Canchaya C and Hardt WD. Phages and the evolution of bacterial pathogens:from genomic rearrangements to lysogenic conversion[J]. Microbiol Mol Biol Rev,2004,68:560-602
18. Faruque SM, Naser IB, Islam MJ, et al. Seasonal epidemics of cholera inversely correlate with the prevalence of environmental cholera phages[J]. Proc Natl Acad Sci U S A,2005,102:1702-7
19.噬菌体分子生物学—基本知识和技能.科学出版社.第一版,2001.
20. Hazelbauer GL. Role of the receptor for bacteriophage lambda in the functioning of the maltose chemoreceptor of Escherichia coli[J]. J Bacteriol, 1975,124:119-26
21. Cole ST,Chen-Schmeisser U, Hindennach I, et al.Apparent bacteriophage-binding region of an Escherichia coli K-12 outer membrane protein[J]. J Bacteriol,1983,153:581-7
22. Yu SL, Ko KL, Chen CS, et al. Characterization of the distal tail fiber locus and determination of the receptor for phage AR1, which specifically infects Escherichia coli O157:H7[J]. J Bacteriol,2000,182:5962-8
23. Ho TD and Slauch JM. OmpC is the receptor for Gifsy-1 and Gifsy-2 bacteriophages of Salmonella[J]. J Bacteriol,2001,183:1495-8
24. Costerton, J.W., Lewandowski, Z., Caldwell, D.E., Korber, D.R., and Lappin-Scott, H.M., (1995) Microbial biofilms. Annu. Rev. Microbiol.49: 711-745.
25. Stoodley, P., Sauer, K., Davies, D.G, and Costerton, J.W. (2002) Biofilms as complex differentiated communities. Annu. Rev. Microbiol.56:187-209.
26. Boyd, A., and Chakrabarty, A.M. (1994) Role of alginate lyase in cell detachment of Pseudomonas aeruginosa. Appl. Environ. Microbiol.60: 2355-2359.
27. Davies, D.G., and Geesey, G.G. (1995) Regulation of the alginate biosynthesis gene algC in Pseudomonas aeruginosa during biofilm development in continuous culture. Appl. Environ. Microbiol.61:860-867.
28. Lawrence, J.R., Korber, D.R., Hoyle, B.D., Costertion, J.W., and Caldwell, D.E. (1991) Optical sectioning of microbial biofilms. J.Bacteriol.173: 6558-6567.
29. Bisweswar Nandi, Ranjan K. Nandy,Amit Sarka.Structural features, properties and regulation of the outer-membrane protein W (OmpW) of Vibrio cholerae. Microbiology (2005),151,2975-2986
30. Cameron DN, Khambaty FM, Wachsmuth IK, et al. Molecular characterization of Vibrio cholerae 01 strains by pulsed-filed gel electrophoresis. J Clin Microbiol,1994,32:1685-1690.
31. Kam KM, Luey CK, Tsang YM, et al. Molecular subtyping of Vibrio cholerae 01 and 0139 by pulsed-field gel electrophoresis in Hong Kong: Correlation with epidemiological events from 1994 to 2002. J Clin Microbiol, 2003,41:4502-4511.
1. Brenner S. The genetics of Caenorhabditis elegans [J].Genetics,1974, 77(7):71-94.
2. Couillault C, Ewbank JJ. Diverse bacteria are pathogens of Caenorhabditis elegans[J]. Infect Immun,2002,70(8):4705-4707.
3. Kamal, A. M.1974. The seventh pandemic of cholera, p.1-14. In D. Barua, and W. Burrows (ed.), Cholera. The W. B. Saunders Co., Philadelphia, Pa.
4. Colwell, R. R., and W. M. Spira.1992. The ecology of Vibrio cholerae, p.107-127. In D. Barua and W. B. Greenough III (ed.), Cholera. Plenum Medical Book Co., New York, N.Y.
5. Klose KE. The suckling mouse model of cholera.Trends Microbiol.2000 Apr;8(4):189-91.
6. Mylonakis E, Aballay A. Worms and flies as genetically tractable animal models to study host-pathogen interactions[J]. Infect Immun.,2005 73(7):3833-3841.
7. Tan MW, Rahme LG, Sternberg JA, et al. Pseudomonas aeruginosa killing of Caenorhabditis elegans used to identify P. aeruginosa virulence factors[J]. Proc Natl Acad Sci USA,1999,96(5):2408-2413.A
8. Bae T, Banger AK, Wallace A, et al. Staphylococcus aureus virulence genes identified by bursa aurealis mutagenesis and nematode killing[J].Proc Natl Acad Sci U S A.,2004,101(33):12312-12317.
9. Sifri CD, Baresch-Bernal A, Calderwood SB, et al. Virulence of Staphylococcus aureus small colony variants in the Caenorhabditis elegans infection model[J]. Infect Immun.,2006,74(2):1091-1096.
10. Bae T, Banger AK, Wallace A, et al. Staphylococcus aureus virulence genes identified by bursa aurealis mutagenesis and nematode killing[J].Proc Natl Acad Sci U S A.,2004,101(33):12312-12317.
11. Sifri CD, Baresch-Bernal A, Calderwood SB, et al. Virulence of Staphylococcus aureus small colony variants in the Caenorhabditis elegans infection model[J]. Infect Immun.,2006,74(2):1091-1096.
12. Burton EA, Pendergast AM, Aballay A. The Caenorhabditis elegans ABL-1 tyrosine kinase is required for Shigella flexneri pathogenesis[J]. Appl Environ Microbiol.,2006,72(7):5043-5051.
13. Lee DG, Urbach JM, Wu G, et al. Genomic analysis reveals that Pseudomonas aeruginosa virulence is combinatorial[J]. Genome Biol.,2006,7(10):R90.
14. Darby C, Chakraborti A, Politz SM, et al. Caenorhabditis elegans mutants resistant to attachment of Yersinia biofilms[J]. Genetics,2007,176(1):221-230.
15. Thomsen LE, Slutz SS, Tan MW,et al. Caenorhabditis elegans is a model host for Listeria monocytogenes[J]. Appl Environ Microbiol,2006 72(2):1700-1701.
16. Paulander W, Pennhag A, Andersson DI, et al. Caenorhabditis elegans as a model to determine fitness of antibiotic-resistant Salmonella enterica serovar typhimurium[J]. Antimicrob Agents Chemother.,2007,51(2):766-769.
17. Chua KL, Chan YY, Gan YH. Flagella are virulence determinants of Burkholderia pseudomallei[J]. Infect Immun,2003,71(4):1622-1629.
18. Jansen WT, Bolm M, Balling R, et al. Hydrogen peroxide-mediated killing of Caenorhabditis elegans by Streptococcus pyogenes[J]. Infect Immun,2002, 70(9):5202-5207.
19. Aballay A, Ausubel FM. Programmed cell death mediated by ced-3 and ced-4 protects Caenorhabditis elegans from Salmonella typhimurium-mediated killing[J].Proc Natl Acad Sci U S A.,2001,98(5):2735-2739.
20. Wei JZ, Hale K, Carta L, et al. Bacillus thuringiensis crystal proteins that target nematodes[J]. Proc Natl Acad Sci U S A,2003,100(5):2760-2765.
21. Schulenburg H, Ewbank JJ. Diversity and specificity in the interaction between Caenorhabditis elegans and the pathogen Serratia marcescens[J].BMC Evol Biol.,2004,4(1):49.
22. Tang RJ, Breger J, Idnurm A, et al. Cryptococcus neoformans gene involved in mammalian pathogenesis identified by a Caenorhabditis elegans progeny-based approach[J].Infect Immun.,2005,73(12):8219-8225.
23. Gravato-Nobre MJ, Nicholas HR, Nijland R, et al. Multiple genes affect sensitivity of Caenorhabditis elegans to the bacterial pathogen Microbacterium nematophilum[J]. Genetics.,2005,171(3):1033-1045.
24. Garsin DA, Sifri CD, Mylonakis E, et al. A simple model host for identifying Gram-positive virulence factors[J]. Proc Natl Acad Sci. USA,2001, 98(19):10892-10897.
25. Tan MW, Rahme LG, Sternberg JA, et al. Pseudomonas aeruginosa killing of Caenorhabditis elegans used to identify P. aeruginosa virulence factors [J]. Proc Natl Acad Sci USA,1999,96(5):2408-2413.
26. Pollitzer, R.1959. History of the disease, p.11-50. In R. Pollitzer (ed.), Cholera. World Health Organization, Geneva, Switzerland.
27. Cohen, J., T. Schwartz, R. Klasmer, D. Pridan, H. Ghalayini, and A. M. Davies.1971. Epidemiological aspects of cholera El Tor outbreak in a non-endemic area. Lancet ii:86-89.
28. Herrington, D. A., R. H. Hall, G. Losonsky, J. J. Mekalanos, R. K. Taylor, and M. M. Levine.1988. Toxin, toxin-coregulated pili and ToxR regulon are essential for Vibrio cholerae pathogenesis in humans. J. Exp. Med.168: 1487-1492.
29. Karolis V, Barbro L, Gangwei O, et al. A Vibrio cholerae protease needed for killing of Caenorhabditis elegans has a role in protection from natural predator grazing[J]. Proc Natl Acad Sci USA,2006;103;9280-9285
30. Beale E, Li G, Tan MW, et al. Caenorhabditis elegans senses bacterial autoinducers[J]. Appl Environ Microbiol.,2006 72(7):5135-5137.
31. Brillard J, Ribeiro C, Boemare N,et al. Two distinct hemolytic activities in Xenorhabdus nematophila are active against immunocompetent insect cells [J]. Appl Environ Microbiol,2001,67:2515-2525.
1. Couillault C, Ewbank JJ. Diverse bacteria are pathogens of Caenorhabditis elegans[J]. Infect Immun,2002,70(8):4705-4707.
2. Brenner S. The genetics of Caenorhabditis elegans [J].Genetics,1974,77(7): 71-94.
3. Lai CH, Chou CY, Chang LY, et al. Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics[J]. Genome Res,2000,10 (5):703-713.
4. Tan MW, Rahme LG, Sternberg JA, et al. Pseudomonas aeruginosa killing of Caenorhabditis elegans used to identify P. aeruginosa virulence factors[J]. Proc Natl Acad Sci USA,1999,96(5):2408-2413.
5. Beale E, Li G, Tan MW, et al. Caenorhabditis elegans senses bacterial autoinducers[J]. Appl Environ Microbiol.,2006 72(7):5135-5137.
6. Garsin DA, Sifri CD, Mylonakis E, et al. A simple model host for identifying Gram-positive virulence factors[J]. Proc Natl Acad Sci. USA,2001, 98(19):10892-10897.
7. Moy TI, Mylonakis E, Calderwood SB, et al. Cytotoxicity of hydrogen peroxide produced by Enterococcus faecium[J]. Infect Immun.,2004 72(8):4512-4520.
8. Bae T, Banger AK, Wallace A, et al. Staphylococcus aureus virulence genes identified by bursa aurealis mutagenesis and nematode killing[J].Proc Natl Acad Sci U S A.,2004,101(33):12312-12317.
9. Sifri CD, Baresch-Bernal A, Calderwood SB, et al. Virulence of Staphylococcus aureus small colony variants in the Caenorhabditis elegans infection model[J]. Infect Immun.,2006,74(2):1091-1096.
10. Burton EA, Pendergast AM, Aballay A. The Caenorhabditis elegans ABL-1 tyrosine kinase is required for Shigella flexneri pathogenesis[J]. Appl Environ Microbiol.,2006,72(7):5043-5051.
11. Lee DG, Urbach JM, Wu G, et al. Genomic analysis reveals that Pseudomonas aeruginosa virulence is combinatorial[J]. Genome Biol., 2006,7(10):R90.
12. Darby C, Chakraborti A, Politz SM, et al. Caenorhabditis elegans mutants resistant to attachment of Yersinia biofilms[J]. Genetics, 2007,176(1):221-230.
13. Thomsen LE, Slutz SS, Tan MW,et al. Caenorhabditis elegans is a model host for Listeria monocytogenes[J]. Appl Environ Microbiol,2006 72(2):1700-1701.
14. Paulander W, Pennhag A, Andersson DI, et al. Caenorhabditis elegans as a model to determine fitness of antibiotic-resistant Salmonella enterica serovar typhimurium[J]. Antimicrob Agents Chemother.,2007,51(2):766-769.
15. Chua KL, Chan YY, Gan YH. Flagella are virulence determinants of Burkholderia pseudomallei[J]. Infect Immun,2003,71(4):1622-1629.
16. Jansen WT, Bolm M, Balling R, et al. Hydrogen peroxide-mediated killing of Caenorhabditis elegans by Streptococcus pyogenes[J]. Infect Immun,2002, 70(9):5202-5207.
17. Aballay A, Ausubel FM. Programmed cell death mediated by ced-3 and ced-4 protects Caenorhabditis elegans from Salmonella typhimurium-mediated killing[J].Proc Natl Acad Sci U S A.,2001,98(5):2735-2739.
18. Wei JZ, Hale K, Carta L, et al. Bacillus thuringiensis crystal proteins that target nematodes[J]. Proc Natl Acad Sci U S A,2003,100(5):2760-2765.
19. Schulenburg H, Ewbank JJ. Diversity and specificity in the interaction between Caenorhabditis elegans and the pathogen Serratia marcescens[J].BMC Evol Biol.,2004,4(1):49.
20. Tang RJ, Breger J, Idnurm A, et al. Cryptococcus neoformans gene involved in mammalian pathogenesis identified by a Caenorhabditis elegans progeny-based approach [J]. Infect Immun.,2005,73(12):8219-8225.
21. Gravato-Nobre MJ, Nicholas HR, Nijland R, et al. Multiple genes affect sensitivity of Caenorhabditis elegans to the bacterial pathogen Microbacterium nematophilum[J]. Genetics.,2005,171(3):1033-1045.
22. Mylonakis E, Aballay A. Worms and flies as genetically tractable animal models to study host-pathogen interactions[J]. Infect Immun.,2005, 73(7):3833-3841.
23. Brillard J, Ribeiro C, Boemare N,et al. Two distinct hemolytic activities in Xenorhabdus nematophila are active against immunocompetent insect cells[J]. Appl Environ Microbiol,2001,67 (6):2515-2525.
24. Vaitkevicius K, Lindmark B, Ou G, et al. A Vibrio cholerae protease needed for killing of Caenorhabditis elegans has a role in protection from natural predator grazing[J]. Proc Natl Acad Sci U S A.,2006,103(24):9280-9285.
25. Mahajan-Miklos S, Rahme LG, Ausubel FM. Elucidating the molecular mechanisms of bacterial virulence using non-mammalian hosts[J]. Mol Microbiol,2000,37 (5):981-988.
2. Pollitzer, R.1959. Cholera. World Health Organization, Geneva.
3. Satcher, D.1995. Emerging infections:getting ahead of the cure. Emerg. Infect. Dis.1:1-6.
4. WHO. Cholera,2004. Wkly Epidem Rec,2005,80:261-268.
5.祝小平,吕强,欧阳兵等.四川省霍乱流行特征及防治对策.中国预防医学杂志,,2001,2(增刊)：133-136.
6.张静,武桂珍,李建东,等.1999年全国霍乱疫情分析.中国预防医学杂志,2001,2(增刊)：4-9.
7.武桂珍,张静,白胡群.2000年全国霍乱疫情分析.中国预防医学杂志,2001,2(增刊)：9-11.
8.王汉章,黄玉英,张静,等.2001年全国霍乱疫情分析.中国预防医学杂志,2003,4(增刊)：13-15.
9.王汉章,黄玉英,张静,等.2002年全国霍乱疫情分析.中国预防医学杂志,2003,4(增刊)：9-12.
10. Guidolin,A., P.A. Manning.1987. Genetics of Vibrio cholerae and its bacteriophages. Microbiol. Rev.51:285-298
11. Kar,S.,R.K.Ghosh,and A.N.Ghosh.1996.integration of the DNA of a novel filamentous bacteriophage VSK from Vibrio cholerae 0139 into the host chromosomal DNA. FEMS Microbiol.Lett.145:17-22
12. Rowe, B., and J. A. Frost.1992. Vibrio phages and phage-typing, p.95-105. In D. Barua and W. B. Greenough, III (ed.), Cholera. Plenum Medical Book Co., New York.
13. Inoue T, Matsuzaki S and Tanaka S. A 26-kDa outer membrane protein, OmpK, common to Vibrio species is the receptor for a broad-host-range vibriophage, KVP40[J]. FEMS Microbiol Lett,1995,125:101-5
14. Prehm P, Jann B, Jann K, et al. On a bacteriophage T3 and T4 receptor region within the cell wall lipopolysaccharide of Escherichia coli B[J]. J Mol Biol, 1976,101:277-81
15. Merino S, Camprubi S and Tomas JM. Isolation and characterization of bacteriophage PM3 from Aeromonas hydrophila the bacterial receptor for which is the monopolar flagellum[J]. FEMS Microbiol Lett,1990,57:277-82
16.中华人民共和国卫生部疾病预防控制司.霍乱防治手册.第五版.1999.
17. Brussow H, Canchaya C and Hardt WD. Phages and the evolution of bacterial pathogens:from genomic rearrangements to lysogenic conversion[J]. Microbiol Mol Biol Rev,2004,68:560-602
18. Faruque SM, Naser IB, Islam MJ, et al. Seasonal epidemics of cholera inversely correlate with the prevalence of environmental cholera phages[J]. Proc Natl Acad Sci U S A,2005,102:1702-7
19.噬菌体分子生物学—基本知识和技能.科学出版社.第一版,2001.
20. Hazelbauer GL. Role of the receptor for bacteriophage lambda in the functioning of the maltose chemoreceptor of Escherichia coli[J]. J Bacteriol, 1975,124:119-26
21. Cole ST,Chen-Schmeisser U, Hindennach I, et al.Apparent bacteriophage-binding region of an Escherichia coli K-12 outer membrane protein[J]. J Bacteriol,1983,153:581-7
22. Yu SL, Ko KL, Chen CS, et al. Characterization of the distal tail fiber locus and determination of the receptor for phage AR1, which specifically infects Escherichia coli O157:H7[J]. J Bacteriol,2000,182:5962-8
23. Ho TD and Slauch JM. OmpC is the receptor for Gifsy-1 and Gifsy-2 bacteriophages of Salmonella[J]. J Bacteriol,2001,183:1495-8
24. Costerton, J.W., Lewandowski, Z., Caldwell, D.E., Korber, D.R., and Lappin-Scott, H.M., (1995) Microbial biofilms. Annu. Rev. Microbiol.49: 711-745.
25. Stoodley, P., Sauer, K., Davies, D.G, and Costerton, J.W. (2002) Biofilms as complex differentiated communities. Annu. Rev. Microbiol.56:187-209.
26. Boyd, A., and Chakrabarty, A.M. (1994) Role of alginate lyase in cell detachment of Pseudomonas aeruginosa. Appl. Environ. Microbiol.60: 2355-2359.
27. Davies, D.G., and Geesey, G.G. (1995) Regulation of the alginate biosynthesis gene algC in Pseudomonas aeruginosa during biofilm development in continuous culture. Appl. Environ. Microbiol.61:860-867.
28. Lawrence, J.R., Korber, D.R., Hoyle, B.D., Costertion, J.W., and Caldwell, D.E. (1991) Optical sectioning of microbial biofilms. J.Bacteriol.173: 6558-6567.
29. Bisweswar Nandi, Ranjan K. Nandy,Amit Sarka.Structural features, properties and regulation of the outer-membrane protein W (OmpW) of Vibrio cholerae. Microbiology (2005),151,2975-2986
30. Cameron DN, Khambaty FM, Wachsmuth IK, et al. Molecular characterization of Vibrio cholerae 01 strains by pulsed-filed gel electrophoresis. J Clin Microbiol,1994,32:1685-1690.
31. Kam KM, Luey CK, Tsang YM, et al. Molecular subtyping of Vibrio cholerae 01 and 0139 by pulsed-field gel electrophoresis in Hong Kong: Correlation with epidemiological events from 1994 to 2002. J Clin Microbiol, 2003,41:4502-4511.
1. Brenner S. The genetics of Caenorhabditis elegans [J].Genetics,1974, 77(7):71-94.
2. Couillault C, Ewbank JJ. Diverse bacteria are pathogens of Caenorhabditis elegans[J]. Infect Immun,2002,70(8):4705-4707.
3. Kamal, A. M.1974. The seventh pandemic of cholera, p.1-14. In D. Barua, and W. Burrows (ed.), Cholera. The W. B. Saunders Co., Philadelphia, Pa.
4. Colwell, R. R., and W. M. Spira.1992. The ecology of Vibrio cholerae, p.107-127. In D. Barua and W. B. Greenough III (ed.), Cholera. Plenum Medical Book Co., New York, N.Y.
5. Klose KE. The suckling mouse model of cholera.Trends Microbiol.2000 Apr;8(4):189-91.
6. Mylonakis E, Aballay A. Worms and flies as genetically tractable animal models to study host-pathogen interactions[J]. Infect Immun.,2005 73(7):3833-3841.
7. Tan MW, Rahme LG, Sternberg JA, et al. Pseudomonas aeruginosa killing of Caenorhabditis elegans used to identify P. aeruginosa virulence factors[J]. Proc Natl Acad Sci USA,1999,96(5):2408-2413.A
8. Bae T, Banger AK, Wallace A, et al. Staphylococcus aureus virulence genes identified by bursa aurealis mutagenesis and nematode killing[J].Proc Natl Acad Sci U S A.,2004,101(33):12312-12317.
9. Sifri CD, Baresch-Bernal A, Calderwood SB, et al. Virulence of Staphylococcus aureus small colony variants in the Caenorhabditis elegans infection model[J]. Infect Immun.,2006,74(2):1091-1096.
10. Bae T, Banger AK, Wallace A, et al. Staphylococcus aureus virulence genes identified by bursa aurealis mutagenesis and nematode killing[J].Proc Natl Acad Sci U S A.,2004,101(33):12312-12317.
11. Sifri CD, Baresch-Bernal A, Calderwood SB, et al. Virulence of Staphylococcus aureus small colony variants in the Caenorhabditis elegans infection model[J]. Infect Immun.,2006,74(2):1091-1096.
12. Burton EA, Pendergast AM, Aballay A. The Caenorhabditis elegans ABL-1 tyrosine kinase is required for Shigella flexneri pathogenesis[J]. Appl Environ Microbiol.,2006,72(7):5043-5051.
13. Lee DG, Urbach JM, Wu G, et al. Genomic analysis reveals that Pseudomonas aeruginosa virulence is combinatorial[J]. Genome Biol.,2006,7(10):R90.
14. Darby C, Chakraborti A, Politz SM, et al. Caenorhabditis elegans mutants resistant to attachment of Yersinia biofilms[J]. Genetics,2007,176(1):221-230.
15. Thomsen LE, Slutz SS, Tan MW,et al. Caenorhabditis elegans is a model host for Listeria monocytogenes[J]. Appl Environ Microbiol,2006 72(2):1700-1701.
16. Paulander W, Pennhag A, Andersson DI, et al. Caenorhabditis elegans as a model to determine fitness of antibiotic-resistant Salmonella enterica serovar typhimurium[J]. Antimicrob Agents Chemother.,2007,51(2):766-769.
17. Chua KL, Chan YY, Gan YH. Flagella are virulence determinants of Burkholderia pseudomallei[J]. Infect Immun,2003,71(4):1622-1629.
18. Jansen WT, Bolm M, Balling R, et al. Hydrogen peroxide-mediated killing of Caenorhabditis elegans by Streptococcus pyogenes[J]. Infect Immun,2002, 70(9):5202-5207.
19. Aballay A, Ausubel FM. Programmed cell death mediated by ced-3 and ced-4 protects Caenorhabditis elegans from Salmonella typhimurium-mediated killing[J].Proc Natl Acad Sci U S A.,2001,98(5):2735-2739.
20. Wei JZ, Hale K, Carta L, et al. Bacillus thuringiensis crystal proteins that target nematodes[J]. Proc Natl Acad Sci U S A,2003,100(5):2760-2765.
21. Schulenburg H, Ewbank JJ. Diversity and specificity in the interaction between Caenorhabditis elegans and the pathogen Serratia marcescens[J].BMC Evol Biol.,2004,4(1):49.
22. Tang RJ, Breger J, Idnurm A, et al. Cryptococcus neoformans gene involved in mammalian pathogenesis identified by a Caenorhabditis elegans progeny-based approach[J].Infect Immun.,2005,73(12):8219-8225.
23. Gravato-Nobre MJ, Nicholas HR, Nijland R, et al. Multiple genes affect sensitivity of Caenorhabditis elegans to the bacterial pathogen Microbacterium nematophilum[J]. Genetics.,2005,171(3):1033-1045.
24. Garsin DA, Sifri CD, Mylonakis E, et al. A simple model host for identifying Gram-positive virulence factors[J]. Proc Natl Acad Sci. USA,2001, 98(19):10892-10897.
25. Tan MW, Rahme LG, Sternberg JA, et al. Pseudomonas aeruginosa killing of Caenorhabditis elegans used to identify P. aeruginosa virulence factors [J]. Proc Natl Acad Sci USA,1999,96(5):2408-2413.
26. Pollitzer, R.1959. History of the disease, p.11-50. In R. Pollitzer (ed.), Cholera. World Health Organization, Geneva, Switzerland.
27. Cohen, J., T. Schwartz, R. Klasmer, D. Pridan, H. Ghalayini, and A. M. Davies.1971. Epidemiological aspects of cholera El Tor outbreak in a non-endemic area. Lancet ii:86-89.
28. Herrington, D. A., R. H. Hall, G. Losonsky, J. J. Mekalanos, R. K. Taylor, and M. M. Levine.1988. Toxin, toxin-coregulated pili and ToxR regulon are essential for Vibrio cholerae pathogenesis in humans. J. Exp. Med.168: 1487-1492.
29. Karolis V, Barbro L, Gangwei O, et al. A Vibrio cholerae protease needed for killing of Caenorhabditis elegans has a role in protection from natural predator grazing[J]. Proc Natl Acad Sci USA,2006;103;9280-9285
30. Beale E, Li G, Tan MW, et al. Caenorhabditis elegans senses bacterial autoinducers[J]. Appl Environ Microbiol.,2006 72(7):5135-5137.
31. Brillard J, Ribeiro C, Boemare N,et al. Two distinct hemolytic activities in Xenorhabdus nematophila are active against immunocompetent insect cells [J]. Appl Environ Microbiol,2001,67:2515-2525.
1. Couillault C, Ewbank JJ. Diverse bacteria are pathogens of Caenorhabditis elegans[J]. Infect Immun,2002,70(8):4705-4707.
2. Brenner S. The genetics of Caenorhabditis elegans [J].Genetics,1974,77(7): 71-94.
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