猪链球菌2型江苏分离株溶血素基因缺失株的构建及特性分析
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摘要
猪链球菌(Streptococcus suis, SS)能引起猪脑膜炎、关节炎、败血症甚至死亡,也可导致生猪从业人员的感染和死亡,是一种重要的人兽共患病病原体。根据荚膜多糖的抗原性差异,猪链球菌分35个血清型,其中猪链球菌2型(SS2)分布最广,分离率最高,致病性最强。
猪链球菌溶血素(亦称猪溶素,简称SLY),是SS2的一种重要毒力因子。SLY阳性菌株的流行存在一定地域性,北美分离株的溶血素阳性率明显低于欧洲、亚洲分离株。提示我们溶血素在不同地域的猪链球菌的致病过程中可能发挥不同的功能。
目前对溶血素的生物学功能和致病机理还不十分明确。除了可以肯定SLY能溶解多种动物的红细胞及对多种细胞有毒性作用外,对溶血素如何诱导细胞因子表达、如何在猪链球菌病(尤其在脑膜炎)的发生和发展起作用,还有待于进一步的深入研究。
本研究对国内病猪中猪链球菌2型分离株的溶血素基因进行了检测及序列分析,明确了其分布及遗传变异情况；并通过原核表达全长溶血素及其生物学特性及免疫原性的研究、猪链球菌2型江苏分离株溶血素基因缺失株的构建及其生物学特性与致病性分析,对溶血素的生物学功能、尤其是对其分子致病机理进行了较为深入的研究。
1国内病猪中猪链球菌2型分离株溶血素基因的PCR检测及序列分析
通过聚合酶链反应(PCR)方法检测29株不同年代、不同地区猪链球菌2型(SS2)国内病猪分离株的溶血素基因(sly),并将其中的5株(SS2-1、HA9801、HA0507、 JR0507和ZY05719)的sly进行克隆及序列分析。结果显示：29株菌都有sly,其中5株菌的sly的ORF的碱基数目都为1,494bp、编码497个氨基酸,核苷酸序列的同源性为99.7%～100.0%,所推导的蛋白质序列的同源性为99.8%～100.0%,其中SS2-1、 HA9801、HA0507、JR0507与国外参考株P1/7的序列完全一致。表明中国猪链球菌2型病猪分离株普遍具有sly,且基因序列极为保守。
2猪链球菌2型溶血素全长基因的原核表达及其生物学特性与免疫原性研究
根据猪链球菌(Streptococcus suis,SS)溶血素的基因序列,设计引物,以江苏分离株SS2-1的基因组为模板,扩增出除信号肽序列外的sly全长基因,并定向克隆到表达载体pET-32α中,转化大肠杆菌BL21(DE3)。重组菌经1mM IPTG诱导,在37℃下,4h时表达产物(分子量约为72kDa)达到高峰,表达量约占菌体总蛋白20%,表达产物在上清和包涵体中各占一半。将上清经镍柱亲和层析纯化,纯化蛋白经Western blotting鉴定呈阳性,对绵羊红细胞、鸡红细胞的溶血效价分别为1.707×105HU/mg.4.267×104HU/mg,并可引起HEp-2和Vero细胞的融合、颗粒增多和脱落。纯化蛋白对BALB/c小鼠的免疫保护性为83.3%(5/6)。这为进一步研究SLY致病机理和研制猪链球菌新型疫苗奠定了基础。
3猪链球菌2型江苏分离株溶血素基因缺失株的构建
以猪链球菌2型江苏分离株JR0507为模板,分别扩增溶血素基因的569bp、559bp的上下游同源臂,以pSET3为模板,扩增了长度为1056bp的氯霉素基因,将三者依次与自杀性质粒pSET4S质粒进行连接,将连接产物转化入DH5a感受态中,构建了基因缺失载体pSET4s△SLY。然后将构建的载体pSET4s△SLY:通过电转化导入JR0507的感受态细胞中,利用氯霉素抗性进行初步筛选,并用PCR和Western blotting进行鉴定,结果成功构建了溶血素基因缺失株JR0507(△SLY),为进一步研究猪链球菌溶血素的功能奠定了基础。
4猪链球菌2型江苏分离株溶血素基因缺失株的生物学特性及致病性分析
对构建好的溶血素基因缺失株JR0507(△SLY)与亲本株JR0507的各项生物学特性及致病性进行了比较研究。结果表明,JR0507(△SLY)已完全失去了溶血活性。与亲本株相比较,其生长特性、生化特性、对PK-15、HEp-2和PIEC细胞的粘附能力没有发生变化,但对这3种细胞的毒性作用都呈极显著下降。缺失株在全血中的存活率为(15.5+2.8)%,亲本株为(40.7+4.8)%,呈极显著下降(P<0.01)。动物致病性试验表明,△SLY对BALB/c小鼠的MLD为1.0×109CFU,比亲本株上升了10倍,同时△SLY对新西兰兔和断乳仔猪都失去了致病性。用细菌接种3D4猪肺泡巨噬细胞6h后,2株菌都不能诱导炎症相关细胞因子(IL-1β、IL-18、IL-8、IL-12和IL-10)的转录,但在接种12h后,亲本株能诱导3D4细胞表达除IL-12外的其它4种细胞因子,而△SLY仍不能诱导这些细胞因子的表达。总之,与亲本株相比,溶血素基因缺失株可引起不同动物的致病性的下降,而引起其毒力下降的原因,与其在血液中的存活能力和对细胞的破坏能力下降、促炎症因子表达减少有关。这些都进一步阐明了溶血素的生物学功能及分子致病机理,说明溶血素在猪链球菌病的发生和发展中起着重要的作用。
Streptococcus suis (S. suis) is a major swine pathogen which is responsible for a wide range of diseases, including septicaemia, meningitis, endocarditis, arthritis and even acute death. In addition to causing disease in pigs, it is also an important zoonotic agent that afflicts people in close contact with infected pigs or pork-derived products. Thirty-five types (1-34and1/2) have been described based on capsular polysaccharides. Streptococcus suis serotype2(SS2) is the most frequently isolated and associated with disease.
Hemolysin (Suilysin, SLY) is an important virulent factor of SS2. Geographical differences in prevalence of sly+strains have been described. The most striking difference is the low prevalence of suilysin positive strains in North America in comparison to Europe and Asia.This reminds us that SLY may play different role in the pathogenicity of different region SS2.
Up to now, the biological function and pathogenic mechanism of SLY is not very clear. It is certain that SLY can lysis many kinds of animal red cells and has toxicity to many cells. It remains to be further elucidated its ability of inducing expression of cytokines and its role of occurrence and development in the disease, especially in meningitis.
In this study, the distribution and genetic variance of suilysin gene of streptococcus suis type2strains isolated from diseased pigs in china was identified.The recombinant full length suilysin was expressed in E.coli and its bioactivity and immunogenicity was analyzed. We constructed the suilysin knock-out mutant of streptococcus suis type2strain isolated in Jiangsu provine and studied its biological characteristics and pathogenicity. All these help us to further understand the biological function of suilysin, especially for its molecular pathogenic mechanism.
1PCR detection and sequence analysis of the gene encoding suilysin from streptococcus suis type2strains isolated from diseased pigs in china
The genes encoding suilysin (SLY) of Streptococcus suis type2strains isolated from diseased pigs in China were detected and sequence analyzed. The genes encoding SLY from the29strains isolated at different time and areas were detected by polymerase chain reaction (PCR). The sly genes of SS2-1, HA9801, HA0507, JR0507and ZY05719were cloned and sequence analyzed. The results were as following:the genes encoding SLY of all29strains were positive by PCR; the ORFs of sly gene of the5strains were comprised of1494base pairs which encoded497amino acids; nucleotide sequence homology were99.7%-100.0%and the derived protein sequence homology were99.8%-100.0%. The sly genes of SS2-1, HA9801, HA0507and JR0507were identical to that of the foreign referenced strain1/7. From the above, it came to the conclusion that the sly gene is prevalent in the Streptococcus suis type2isolates from diseased pigs in China and the sequence of sly gene is extremely conservative.
2Prokaryotic expression, bioactivity and immunogenicity of the full length suilysin of streptococcus suis type2
The suilysin full length gene of Streptococcus suis type2was construction by the methods of molecular biology and was cloned into plasmid pET-32a.The recombinatant plamsid was transformed into the expression host strain E.coli BL21(DE3).After4hour induced by1mM IPTG at37℃, the protein which molecular weight was about72K was at the highest level. The content of the protein was about20%of that of total bacterial proteins. The proteins in sonicated supernatant accounted for50%. The purified protein by Ni-NTA His resin was positive by Western blotting. Its hemolytice titer to sheep red cell and chick red cell attained1.707×105HU/mg and4.267×104HU/mg, respectively. The purified protein could cause the Vero cell or HEp-2cell fusion, grain increase and fall. The protection rate of rSLY to BALB/c mice was83.3%(5/6). This established a solid foundation for further research such as pathogenesis and vaccine development.
3Construction of suilysin gene mutation of streptococcus suis type2strain isolated in Jiangsu province
Using the genomic DNA of JR0507as the template,569bp (upstream sly arm) and559bp (downstream sly arm) fragments were amplified, respectively. The cat gene was amplified according to the pSET3DNA. The homologous arms and the cat gene were linked to pSET4S by turns, and then the linked products were transferred into DH5a competent cells to construction the vectors pSET4sΔSLY. Subsequencely pSET4sΔSLY were introducted into competent cells of JR0507by electrotransformation. And the transformants were screened on the plates containing chloromycetin and detected by PCR and Western blotting. The results showed that JR0507(ΔSLY) was successfully constructed, which laid the foundation of studying function of suilysin.
4Analysis of biological characteristics and pathogenicity of suilysin knock-out mutant of Streptococcus suis type2strain isolated in Jiangsu province
The biological characteristics and pathogenicity of JR0507(ΔSLY) and wild type JR0507(WT) was compared. The results showed that the hemolytic activity of JR0507(ASLY) were lost completely. Compared with WT, growth and biochemical characteristics and adhesion ability to PK-15, HEp-2and PIEC cell of the mutant had not changed. But the mutant exhibited a significant decrease toxicity to the cells (P<0.01). The percent survival rate of the wild type parent strain was (40.7±4.8)%in whole blood. In contrast, the mutant was much more sensitive, with a percent survival rate of only (15.5±2.8)%. Animal pathogenicity tests showed that the MLD of ΔSLY to BALB/c mice was1.0×109CFU, ten-fold higher than that of the wild type. And the mutant showed no pathogenicity to New Zealand rabbit and weaning piglet. After6hours incubation,3D4porcine alveolar macrophages expressed no inflammation related cytokines of IL-1β, IL-18, IL-8, IL-12and IL-10by the mutant and WT. But after12hours incubation,3D4expressed the four cytokines except IL-12by field strain, but not by the mutant. In short, the virulence of suilysin knock-out mutant is attenuated when compared with the WT, which may be associated with its decreased ability to survive in whole blood, destruct to cell and induce the express of inflammation related cytokines. All are further clarified the biological function and molecular pathogenic mechanism of hemolysin and proved its important role in the occurrence and development of the disease associated with Streptococcus suis.
猪链球菌溶血素(亦称猪溶素,简称SLY),是SS2的一种重要毒力因子。SLY阳性菌株的流行存在一定地域性,北美分离株的溶血素阳性率明显低于欧洲、亚洲分离株。提示我们溶血素在不同地域的猪链球菌的致病过程中可能发挥不同的功能。
目前对溶血素的生物学功能和致病机理还不十分明确。除了可以肯定SLY能溶解多种动物的红细胞及对多种细胞有毒性作用外,对溶血素如何诱导细胞因子表达、如何在猪链球菌病(尤其在脑膜炎)的发生和发展起作用,还有待于进一步的深入研究。
本研究对国内病猪中猪链球菌2型分离株的溶血素基因进行了检测及序列分析,明确了其分布及遗传变异情况；并通过原核表达全长溶血素及其生物学特性及免疫原性的研究、猪链球菌2型江苏分离株溶血素基因缺失株的构建及其生物学特性与致病性分析,对溶血素的生物学功能、尤其是对其分子致病机理进行了较为深入的研究。
1国内病猪中猪链球菌2型分离株溶血素基因的PCR检测及序列分析
通过聚合酶链反应(PCR)方法检测29株不同年代、不同地区猪链球菌2型(SS2)国内病猪分离株的溶血素基因(sly),并将其中的5株(SS2-1、HA9801、HA0507、 JR0507和ZY05719)的sly进行克隆及序列分析。结果显示：29株菌都有sly,其中5株菌的sly的ORF的碱基数目都为1,494bp、编码497个氨基酸,核苷酸序列的同源性为99.7%～100.0%,所推导的蛋白质序列的同源性为99.8%～100.0%,其中SS2-1、 HA9801、HA0507、JR0507与国外参考株P1/7的序列完全一致。表明中国猪链球菌2型病猪分离株普遍具有sly,且基因序列极为保守。
2猪链球菌2型溶血素全长基因的原核表达及其生物学特性与免疫原性研究
根据猪链球菌(Streptococcus suis,SS)溶血素的基因序列,设计引物,以江苏分离株SS2-1的基因组为模板,扩增出除信号肽序列外的sly全长基因,并定向克隆到表达载体pET-32α中,转化大肠杆菌BL21(DE3)。重组菌经1mM IPTG诱导,在37℃下,4h时表达产物(分子量约为72kDa)达到高峰,表达量约占菌体总蛋白20%,表达产物在上清和包涵体中各占一半。将上清经镍柱亲和层析纯化,纯化蛋白经Western blotting鉴定呈阳性,对绵羊红细胞、鸡红细胞的溶血效价分别为1.707×105HU/mg.4.267×104HU/mg,并可引起HEp-2和Vero细胞的融合、颗粒增多和脱落。纯化蛋白对BALB/c小鼠的免疫保护性为83.3%(5/6)。这为进一步研究SLY致病机理和研制猪链球菌新型疫苗奠定了基础。
3猪链球菌2型江苏分离株溶血素基因缺失株的构建
以猪链球菌2型江苏分离株JR0507为模板,分别扩增溶血素基因的569bp、559bp的上下游同源臂,以pSET3为模板,扩增了长度为1056bp的氯霉素基因,将三者依次与自杀性质粒pSET4S质粒进行连接,将连接产物转化入DH5a感受态中,构建了基因缺失载体pSET4s△SLY。然后将构建的载体pSET4s△SLY:通过电转化导入JR0507的感受态细胞中,利用氯霉素抗性进行初步筛选,并用PCR和Western blotting进行鉴定,结果成功构建了溶血素基因缺失株JR0507(△SLY),为进一步研究猪链球菌溶血素的功能奠定了基础。
4猪链球菌2型江苏分离株溶血素基因缺失株的生物学特性及致病性分析
对构建好的溶血素基因缺失株JR0507(△SLY)与亲本株JR0507的各项生物学特性及致病性进行了比较研究。结果表明,JR0507(△SLY)已完全失去了溶血活性。与亲本株相比较,其生长特性、生化特性、对PK-15、HEp-2和PIEC细胞的粘附能力没有发生变化,但对这3种细胞的毒性作用都呈极显著下降。缺失株在全血中的存活率为(15.5+2.8)%,亲本株为(40.7+4.8)%,呈极显著下降(P<0.01)。动物致病性试验表明,△SLY对BALB/c小鼠的MLD为1.0×109CFU,比亲本株上升了10倍,同时△SLY对新西兰兔和断乳仔猪都失去了致病性。用细菌接种3D4猪肺泡巨噬细胞6h后,2株菌都不能诱导炎症相关细胞因子(IL-1β、IL-18、IL-8、IL-12和IL-10)的转录,但在接种12h后,亲本株能诱导3D4细胞表达除IL-12外的其它4种细胞因子,而△SLY仍不能诱导这些细胞因子的表达。总之,与亲本株相比,溶血素基因缺失株可引起不同动物的致病性的下降,而引起其毒力下降的原因,与其在血液中的存活能力和对细胞的破坏能力下降、促炎症因子表达减少有关。这些都进一步阐明了溶血素的生物学功能及分子致病机理,说明溶血素在猪链球菌病的发生和发展中起着重要的作用。
Streptococcus suis (S. suis) is a major swine pathogen which is responsible for a wide range of diseases, including septicaemia, meningitis, endocarditis, arthritis and even acute death. In addition to causing disease in pigs, it is also an important zoonotic agent that afflicts people in close contact with infected pigs or pork-derived products. Thirty-five types (1-34and1/2) have been described based on capsular polysaccharides. Streptococcus suis serotype2(SS2) is the most frequently isolated and associated with disease.
Hemolysin (Suilysin, SLY) is an important virulent factor of SS2. Geographical differences in prevalence of sly+strains have been described. The most striking difference is the low prevalence of suilysin positive strains in North America in comparison to Europe and Asia.This reminds us that SLY may play different role in the pathogenicity of different region SS2.
Up to now, the biological function and pathogenic mechanism of SLY is not very clear. It is certain that SLY can lysis many kinds of animal red cells and has toxicity to many cells. It remains to be further elucidated its ability of inducing expression of cytokines and its role of occurrence and development in the disease, especially in meningitis.
In this study, the distribution and genetic variance of suilysin gene of streptococcus suis type2strains isolated from diseased pigs in china was identified.The recombinant full length suilysin was expressed in E.coli and its bioactivity and immunogenicity was analyzed. We constructed the suilysin knock-out mutant of streptococcus suis type2strain isolated in Jiangsu provine and studied its biological characteristics and pathogenicity. All these help us to further understand the biological function of suilysin, especially for its molecular pathogenic mechanism.
1PCR detection and sequence analysis of the gene encoding suilysin from streptococcus suis type2strains isolated from diseased pigs in china
The genes encoding suilysin (SLY) of Streptococcus suis type2strains isolated from diseased pigs in China were detected and sequence analyzed. The genes encoding SLY from the29strains isolated at different time and areas were detected by polymerase chain reaction (PCR). The sly genes of SS2-1, HA9801, HA0507, JR0507and ZY05719were cloned and sequence analyzed. The results were as following:the genes encoding SLY of all29strains were positive by PCR; the ORFs of sly gene of the5strains were comprised of1494base pairs which encoded497amino acids; nucleotide sequence homology were99.7%-100.0%and the derived protein sequence homology were99.8%-100.0%. The sly genes of SS2-1, HA9801, HA0507and JR0507were identical to that of the foreign referenced strain1/7. From the above, it came to the conclusion that the sly gene is prevalent in the Streptococcus suis type2isolates from diseased pigs in China and the sequence of sly gene is extremely conservative.
2Prokaryotic expression, bioactivity and immunogenicity of the full length suilysin of streptococcus suis type2
The suilysin full length gene of Streptococcus suis type2was construction by the methods of molecular biology and was cloned into plasmid pET-32a.The recombinatant plamsid was transformed into the expression host strain E.coli BL21(DE3).After4hour induced by1mM IPTG at37℃, the protein which molecular weight was about72K was at the highest level. The content of the protein was about20%of that of total bacterial proteins. The proteins in sonicated supernatant accounted for50%. The purified protein by Ni-NTA His resin was positive by Western blotting. Its hemolytice titer to sheep red cell and chick red cell attained1.707×105HU/mg and4.267×104HU/mg, respectively. The purified protein could cause the Vero cell or HEp-2cell fusion, grain increase and fall. The protection rate of rSLY to BALB/c mice was83.3%(5/6). This established a solid foundation for further research such as pathogenesis and vaccine development.
3Construction of suilysin gene mutation of streptococcus suis type2strain isolated in Jiangsu province
Using the genomic DNA of JR0507as the template,569bp (upstream sly arm) and559bp (downstream sly arm) fragments were amplified, respectively. The cat gene was amplified according to the pSET3DNA. The homologous arms and the cat gene were linked to pSET4S by turns, and then the linked products were transferred into DH5a competent cells to construction the vectors pSET4sΔSLY. Subsequencely pSET4sΔSLY were introducted into competent cells of JR0507by electrotransformation. And the transformants were screened on the plates containing chloromycetin and detected by PCR and Western blotting. The results showed that JR0507(ΔSLY) was successfully constructed, which laid the foundation of studying function of suilysin.
4Analysis of biological characteristics and pathogenicity of suilysin knock-out mutant of Streptococcus suis type2strain isolated in Jiangsu province
The biological characteristics and pathogenicity of JR0507(ΔSLY) and wild type JR0507(WT) was compared. The results showed that the hemolytic activity of JR0507(ASLY) were lost completely. Compared with WT, growth and biochemical characteristics and adhesion ability to PK-15, HEp-2and PIEC cell of the mutant had not changed. But the mutant exhibited a significant decrease toxicity to the cells (P<0.01). The percent survival rate of the wild type parent strain was (40.7±4.8)%in whole blood. In contrast, the mutant was much more sensitive, with a percent survival rate of only (15.5±2.8)%. Animal pathogenicity tests showed that the MLD of ΔSLY to BALB/c mice was1.0×109CFU, ten-fold higher than that of the wild type. And the mutant showed no pathogenicity to New Zealand rabbit and weaning piglet. After6hours incubation,3D4porcine alveolar macrophages expressed no inflammation related cytokines of IL-1β, IL-18, IL-8, IL-12and IL-10by the mutant and WT. But after12hours incubation,3D4expressed the four cytokines except IL-12by field strain, but not by the mutant. In short, the virulence of suilysin knock-out mutant is attenuated when compared with the WT, which may be associated with its decreased ability to survive in whole blood, destruct to cell and induce the express of inflammation related cytokines. All are further clarified the biological function and molecular pathogenic mechanism of hemolysin and proved its important role in the occurrence and development of the disease associated with Streptococcus suis.
引文
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