应用蛋白质芯片技术分析鼠疫耶尔森菌致病相关蛋白抗体表达谱的实验研究
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摘要
鼠疫是一种严重危害人类健康的烈性自然疫源性传染病。历史上曾发生过三次鼠疫大流行，导致至少1.6亿人死亡。鼠疫的致病病原体为鼠疫耶尔森菌(Y.pestis)，属于肠杆菌科(Enterobacteraceae)耶尔森菌属(Yersinia)，该属现包括11个菌种，除鼠疫耶尔森菌、假结核耶尔森菌(Y.pseudotuberculosis)、小肠结肠炎耶尔森菌(Y.enterocolitica)对人致病外，其余8个菌种只对动物致病。
鼠疫主要经鼠蚤叮咬而传播，传染性强，病死率高，呈世界性分布，危害极大。近年来，全世界每年都有几千例病例报告，因此，2000年世界卫生组织将鼠疫列为重新抬头的传染病。1994年印度古吉拉特邦苏拉特市爆发鼠疫流行表明，即使是在现代公共卫生条件下，鼠疫仍有可能侵入大城市，造成严重的爆发流行。此外，鼠疫耶尔森菌还是传统的重要生物战剂，是国际恐怖分子可能用于制造生物恐怖的首选微生物之一。长期以来人们一直致力于鼠疫疫苗的研发，以对付这种自古以来就令人生畏的疾病。
当今世界曾经应用于人体免疫的鼠疫疫苗大体上可分为死菌苗、活菌苗两大类。最初的鼠疫死菌苗出自鼠疫正在肆虐的印度(1897)，而在越南战争(1961-1971)中得到较为广泛应用的鼠疫死菌苗为美军的USP疫苗。但近期的动物学研究表明，死菌苗对肺鼠疫的保护效果较差。鼠疫减毒活菌苗出现于1908年，在20世纪下半叶减毒的EV76活菌苗在许多国家广为使用。但由于EV76不是无毒株，在使用安全性方面存在许多隐患，因此许多国家已不再使用。到目前为止，尚无足够研究数据可以评价任何一种鼠疫疫苗的有效性和安全性，而且上述疫苗还伴有严重的副作用。所以发展一种安全、有效的鼠疫疫苗是当务之急。近年来，鼠疫疫苗的研发工作主要集中在新型减毒活疫苗株的选育和重组基因工程亚单位疫苗的研制上。
理论上讲，任何暴露于免疫系统的细菌抗原都有可能成为候选疫苗组分，但如果应用传统的研究手段一次只能对有限的几种抗原进行分析，而且如果体内和体外实验证实这几种抗原中没有候选疫苗组分的话就需要重新开始新一轮筛选，通常这又需要几年的时间。
在基因组时代，候选疫苗组分的筛选和鉴定一般分为以下4个步骤：(1)
从基因组中选定一系列基因;(2)对选定基因进行大规模的克隆和表达;
(3)对获得的重组蛋白进行纯化;(4)体内和体外分析，评价其免疫效果。
目的基因的筛选是疫苗研发过程中的关键步骤之一，通常可能编码毒力因
子、分泌性抗原、膜相关性抗原的基因可通过以下策略选定:(l)用生物
信息学软件对全基因组序列进行比对后选定;(2)通过蛋白质组技术(如
二维电泳技术、质谱技术)选定;(3)通过体内表达技术(in vivo exPression
teehnolo罗，wET)，条码标示诱变技术(signattire一tagged mutagenesis，
STM)，DNA芯片技术选定。
蛋白质芯片分析技术是一种大规模、平行、快速的蛋白质分析技术平
台，它可以同时对几千种蛋白质进行平行的分析。抗原芯片的研制，使同
时研究机体对细菌全部蛋白质的体液免疫反应成为可能。这为候选疫苗的
鉴定以及疾病的早期血清学诊断奠定了基础。因此利用蛋白质芯片技术，
通过间接FLISA法就可以对感染血清中是否存在能与纯化抗原发生反应的
组分进行鉴定。
本研究首先运用生物信息学技术，并结合鼠疫耶尔森菌基因组学和比
较基因组学的初步研究结果，选择了57个可能编码外膜蛋白、粘附蛋白、
侵袭性蛋白和对宿主细胞毒性的基因作为拟克隆和表达的目的基因。通过
PCR技术、基因克隆和表达技术将上述目的基因克隆入表达载体
PET32此L21中，获得了47个可以在大肠杆菌中正确表达目的蛋白的重组
克隆子，其表达的目的蛋白占菌体总蛋白的30%一50%。目的蛋白经Ni~NTA
纯化试剂盒纯化后纯度均大于85%。这些纯化的蛋白质作为探针被固定在
玻片上制成鼠疫耶尔森菌致病相关蛋白芯片。
此芯片再与定期收集的经鼠疫耶尔森菌免疫的动物血清(新西兰兔、
羊)或自然感染鼠疫动物(狗)血清进行FLISA反应，反应结果经扫读后
进行数据分析。由此可实现对待测血清样品中鼠疫耶尔森菌致病相关蛋白
相应抗体的平行检测，用以比较上述动物体内各种鼠疫耶尔森菌致病相关
蛋白相应抗体出现的速度、滴度以及持续时间的差异。同时还可以比较上
述各种致病相关蛋白在不同种属的实验动物中免疫性的差异。
研究结果显示，动物体内针对FI，o哪A(YPo1435)，LPp(Ypo2394)
抗原的抗体反应较强，没有检测到针对Pla，Y叩T(YPCDI.20)，TyeA
(YPeD 1 .35)，vi‘(钾eol.48)，YPoZ19o，钾03319等抗原的抗体反应。
一5-
除了FI，omp^(YP01435)，LPp(YPo2394)以外，YopE(YPCDI.o6)，
YopK(YpCD 1 .19)，YopD(YPCDI.28)，YoPN(YPCDI.39)，YopR
(YPCDI.57)，Ymt(YPMTI.74)，YP01303，YP01411，YP02945也
能刺激机体产生一定水平的抗体。
研究结果还表明重组蛋白Fl，o娜A(YPo 1435)，L即(钟02394)
有可能用于鼠疫感染的血清学诊断。Y叩E(YPCD 1 .06)，Y叩K
(YPCD 1 .19)，YopD(YPCD 1 .28)，YoPN(YpCDI.39)，YopR
(YPCDI.57)，Ymt(Y
Plague is an ancient disease which has caused over 160 million human deaths in the past and has not been eradicated from the modern world. The etiological agent of plague is Yersinia pestis. Y. pestis is one of ll species of the genus Yersinia. Three members of the genus are pathogenic to humans: Y.pestis, Y. pseudotuberculosis and Y. enterocolitica.
Plague is usually contracted by human as a result of the bite of an infected flea. Each year there are several thousand reported cases of the disease world-wide and plague has been classified as a re-emerging disease by the World Health Organization. Endemic areas for the disease exist in China, Africa, Asia and South America. The Surat outbreak of plague in India in 1994 reminded the world of the threat of this horrible disease. Plague is an international public health risk and a notifiable disease. More over, Y. pestis has been of concern as one of the microorganisms which might be used illegitimately as a bioterrorisim agent against civilian or military communities.
Because of the increasing plague casers and the likelihood of illegitimate use of Y. pestis, there is a requirement for an effective vaccine which can protect human against both bubonic and pneumonic plague.
There are two kinds of vaccines have been used in human, live attenuated vaccine and killed whole cells vaccine (KWC) .The earliest report of a killed whole cell vaccine against plague was in 1897, and USP (a KWC vaccine) had been used in Vietnam during the period 1961-1971. But recent studies in animals have shown that this vaccine offers poor protection against pneumonic disease. Another vaccine, live attenuated vaccine ( EV76 strain) , has been in use since 1908, and was used hi many countries in the late 20 century. However, as EV76 is not fully avirulent, the safety of this vaccine in human is questionable. Today EV76 is considered unsuitable for humans in most countries. The efficacy and the safety of existing vaccines are not proven, and the use of these vaccines is known to be associated with adverse side effects.
-7-
Therefore there is an urgent need for an more efficacious plague vaccine.
In recent years, efforts have focused on the development of a fully recombinant subunit vaccine for plague and the identification of a rationally attenuated mutant strain of Y. pestis.
Theoretically speaking, any bacterial antigen exposed to the immune system represents a potential vaccine candidate. Anyway, only a few antigens can be analyzed simultaneously using conventional approach, and if negative results were obtained from in vitro and in vivo models, the process must repeated from the beginning, which often costs several years to get an ideal result.
in the post-genomics era, three new strategies have been used to identify vaccine candidates. The three strategies share the same four basic steps: (1) selection of a set of genes from the whole genome; (2) high throughput cloning and expression of the selected genes; (3 ) purification of the recombinant proteins; and (4) in vitro and in vivo assays for identification of candidates.
The virulence-associated genes selection is considered to be an important step in vaccine discovery. The three strategies differ in the way to select virulence-associated genes. According to the first strategy, genes are selected in silico utilizing algorithms that can predict genes encoding secreted and surface-associated antigens and virulence factors. These proteins are considered the most relevant for the induction of a protective immune response. Using the second approach, surface-exposed antigens are selected experimentally through the characterization of protein fractions using proteomics techniques such as two-dimensional gel electrophoresis (2D-GE) and mass spectrometry. The third approach is aimed at the identification of invasion and virulence-associated antigens and makes use of several new technologies including in vivo expression technology (IVET), signature-tagged mutagenesis ( STM) and DNA microarray technology.
Protein microarray analysis offers a se
鼠疫主要经鼠蚤叮咬而传播，传染性强，病死率高，呈世界性分布，危害极大。近年来，全世界每年都有几千例病例报告，因此，2000年世界卫生组织将鼠疫列为重新抬头的传染病。1994年印度古吉拉特邦苏拉特市爆发鼠疫流行表明，即使是在现代公共卫生条件下，鼠疫仍有可能侵入大城市，造成严重的爆发流行。此外，鼠疫耶尔森菌还是传统的重要生物战剂，是国际恐怖分子可能用于制造生物恐怖的首选微生物之一。长期以来人们一直致力于鼠疫疫苗的研发，以对付这种自古以来就令人生畏的疾病。
当今世界曾经应用于人体免疫的鼠疫疫苗大体上可分为死菌苗、活菌苗两大类。最初的鼠疫死菌苗出自鼠疫正在肆虐的印度(1897)，而在越南战争(1961-1971)中得到较为广泛应用的鼠疫死菌苗为美军的USP疫苗。但近期的动物学研究表明，死菌苗对肺鼠疫的保护效果较差。鼠疫减毒活菌苗出现于1908年，在20世纪下半叶减毒的EV76活菌苗在许多国家广为使用。但由于EV76不是无毒株，在使用安全性方面存在许多隐患，因此许多国家已不再使用。到目前为止，尚无足够研究数据可以评价任何一种鼠疫疫苗的有效性和安全性，而且上述疫苗还伴有严重的副作用。所以发展一种安全、有效的鼠疫疫苗是当务之急。近年来，鼠疫疫苗的研发工作主要集中在新型减毒活疫苗株的选育和重组基因工程亚单位疫苗的研制上。
理论上讲，任何暴露于免疫系统的细菌抗原都有可能成为候选疫苗组分，但如果应用传统的研究手段一次只能对有限的几种抗原进行分析，而且如果体内和体外实验证实这几种抗原中没有候选疫苗组分的话就需要重新开始新一轮筛选，通常这又需要几年的时间。
在基因组时代，候选疫苗组分的筛选和鉴定一般分为以下4个步骤：(1)
从基因组中选定一系列基因;(2)对选定基因进行大规模的克隆和表达;
(3)对获得的重组蛋白进行纯化;(4)体内和体外分析，评价其免疫效果。
目的基因的筛选是疫苗研发过程中的关键步骤之一，通常可能编码毒力因
子、分泌性抗原、膜相关性抗原的基因可通过以下策略选定:(l)用生物
信息学软件对全基因组序列进行比对后选定;(2)通过蛋白质组技术(如
二维电泳技术、质谱技术)选定;(3)通过体内表达技术(in vivo exPression
teehnolo罗，wET)，条码标示诱变技术(signattire一tagged mutagenesis，
STM)，DNA芯片技术选定。
蛋白质芯片分析技术是一种大规模、平行、快速的蛋白质分析技术平
台，它可以同时对几千种蛋白质进行平行的分析。抗原芯片的研制，使同
时研究机体对细菌全部蛋白质的体液免疫反应成为可能。这为候选疫苗的
鉴定以及疾病的早期血清学诊断奠定了基础。因此利用蛋白质芯片技术，
通过间接FLISA法就可以对感染血清中是否存在能与纯化抗原发生反应的
组分进行鉴定。
本研究首先运用生物信息学技术，并结合鼠疫耶尔森菌基因组学和比
较基因组学的初步研究结果，选择了57个可能编码外膜蛋白、粘附蛋白、
侵袭性蛋白和对宿主细胞毒性的基因作为拟克隆和表达的目的基因。通过
PCR技术、基因克隆和表达技术将上述目的基因克隆入表达载体
PET32此L21中，获得了47个可以在大肠杆菌中正确表达目的蛋白的重组
克隆子，其表达的目的蛋白占菌体总蛋白的30%一50%。目的蛋白经Ni~NTA
纯化试剂盒纯化后纯度均大于85%。这些纯化的蛋白质作为探针被固定在
玻片上制成鼠疫耶尔森菌致病相关蛋白芯片。
此芯片再与定期收集的经鼠疫耶尔森菌免疫的动物血清(新西兰兔、
羊)或自然感染鼠疫动物(狗)血清进行FLISA反应，反应结果经扫读后
进行数据分析。由此可实现对待测血清样品中鼠疫耶尔森菌致病相关蛋白
相应抗体的平行检测，用以比较上述动物体内各种鼠疫耶尔森菌致病相关
蛋白相应抗体出现的速度、滴度以及持续时间的差异。同时还可以比较上
述各种致病相关蛋白在不同种属的实验动物中免疫性的差异。
研究结果显示，动物体内针对FI，o哪A(YPo1435)，LPp(Ypo2394)
抗原的抗体反应较强，没有检测到针对Pla，Y叩T(YPCDI.20)，TyeA
(YPeD 1 .35)，vi‘(钾eol.48)，YPoZ19o，钾03319等抗原的抗体反应。
一5-
除了FI，omp^(YP01435)，LPp(YPo2394)以外，YopE(YPCDI.o6)，
YopK(YpCD 1 .19)，YopD(YPCDI.28)，YoPN(YPCDI.39)，YopR
(YPCDI.57)，Ymt(YPMTI.74)，YP01303，YP01411，YP02945也
能刺激机体产生一定水平的抗体。
研究结果还表明重组蛋白Fl，o娜A(YPo 1435)，L即(钟02394)
有可能用于鼠疫感染的血清学诊断。Y叩E(YPCD 1 .06)，Y叩K
(YPCD 1 .19)，YopD(YPCD 1 .28)，YoPN(YpCDI.39)，YopR
(YPCDI.57)，Ymt(Y
Plague is an ancient disease which has caused over 160 million human deaths in the past and has not been eradicated from the modern world. The etiological agent of plague is Yersinia pestis. Y. pestis is one of ll species of the genus Yersinia. Three members of the genus are pathogenic to humans: Y.pestis, Y. pseudotuberculosis and Y. enterocolitica.
Plague is usually contracted by human as a result of the bite of an infected flea. Each year there are several thousand reported cases of the disease world-wide and plague has been classified as a re-emerging disease by the World Health Organization. Endemic areas for the disease exist in China, Africa, Asia and South America. The Surat outbreak of plague in India in 1994 reminded the world of the threat of this horrible disease. Plague is an international public health risk and a notifiable disease. More over, Y. pestis has been of concern as one of the microorganisms which might be used illegitimately as a bioterrorisim agent against civilian or military communities.
Because of the increasing plague casers and the likelihood of illegitimate use of Y. pestis, there is a requirement for an effective vaccine which can protect human against both bubonic and pneumonic plague.
There are two kinds of vaccines have been used in human, live attenuated vaccine and killed whole cells vaccine (KWC) .The earliest report of a killed whole cell vaccine against plague was in 1897, and USP (a KWC vaccine) had been used in Vietnam during the period 1961-1971. But recent studies in animals have shown that this vaccine offers poor protection against pneumonic disease. Another vaccine, live attenuated vaccine ( EV76 strain) , has been in use since 1908, and was used hi many countries in the late 20 century. However, as EV76 is not fully avirulent, the safety of this vaccine in human is questionable. Today EV76 is considered unsuitable for humans in most countries. The efficacy and the safety of existing vaccines are not proven, and the use of these vaccines is known to be associated with adverse side effects.
-7-
Therefore there is an urgent need for an more efficacious plague vaccine.
In recent years, efforts have focused on the development of a fully recombinant subunit vaccine for plague and the identification of a rationally attenuated mutant strain of Y. pestis.
Theoretically speaking, any bacterial antigen exposed to the immune system represents a potential vaccine candidate. Anyway, only a few antigens can be analyzed simultaneously using conventional approach, and if negative results were obtained from in vitro and in vivo models, the process must repeated from the beginning, which often costs several years to get an ideal result.
in the post-genomics era, three new strategies have been used to identify vaccine candidates. The three strategies share the same four basic steps: (1) selection of a set of genes from the whole genome; (2) high throughput cloning and expression of the selected genes; (3 ) purification of the recombinant proteins; and (4) in vitro and in vivo assays for identification of candidates.
The virulence-associated genes selection is considered to be an important step in vaccine discovery. The three strategies differ in the way to select virulence-associated genes. According to the first strategy, genes are selected in silico utilizing algorithms that can predict genes encoding secreted and surface-associated antigens and virulence factors. These proteins are considered the most relevant for the induction of a protective immune response. Using the second approach, surface-exposed antigens are selected experimentally through the characterization of protein fractions using proteomics techniques such as two-dimensional gel electrophoresis (2D-GE) and mass spectrometry. The third approach is aimed at the identification of invasion and virulence-associated antigens and makes use of several new technologies including in vivo expression technology (IVET), signature-tagged mutagenesis ( STM) and DNA microarray technology.
Protein microarray analysis offers a se
引文
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2．张春华 俞东征 鼠疫病原学 中国地方病防治杂志编辑部1999 内部资料
3 李书宝 戴绘 世界鼠疫疫情态势及研究进展 中国地方病防治杂志 2000；15(1)：21-26
4 俞东征 震惊世界的苏特拉鼠疫流行及其教训 疾病监测杂志 1995 10：104-107
5 Campbell G and Hughes J Plague in india: a new warning from an old nemesis. ann Intern Med. 1995; 122:151-153
6 WHO human plague in 1998 and 1999 weekly epidemiological record 2000 75: 338-343
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8 张贵军 房静 刘振才 1991—2000年我国人间鼠疫疫情分析 中国地方病防治杂志 2003 18(1)：34-37
9 Bossi P and Bricaire F [The plague possible bioterrorist act] Presse Med. 2003 32(17): 804-807
10 Josko D Yersinia pestis: still a plague in the 21st century Clin Lab Sci 2004 17(1): 25-29
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12 Achtman M, Zurth K, Morelli G et al. Yersiniapestis the cause of plague is a recently emerged clone of Yersinia pseudotuberculosis. Proe. Natl. Acad. Sci. USA 1999; 96(24): 14043-14048
13 Parkhill J, Wren BW, Thomson NR et al. Genome sequence of Yersinia pestis the causative agent of plague. Nature 2001; 413(6855): 523-527
14 Deng W, BudandV, Plunkett 3rd G etal. Genome sequence of Yersinia pestis KIM. J Bacteriol. 2002; 184(16): 4601-4611
15 宋亚军 鼠疫耶尔森菌布氏田鼠疫源地菌株91001全基因组序列测定及初步分析博士学位论文 军事医学科学院 2003
16 宋亚军 童宗中 王津 等 鼠疫耶尔森菌菌株91001全基因组序列测定及初步分析 解放军医学杂志2004；29(3)：192-199
17 杨瑞馥 黄培堂 鼠疫耶尔森菌比较和进化基因组学研究 解放军医学杂志2004；29(3)：189-191
18 童宗中 周冬生 宋亚军 等 鼠疫耶尔森菌pgm位点及其侧翼序列遗传变异的比较分析 解放军医学杂志2004；29(4)：300-306
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