口服表达幽门螺杆菌抗原的重组乳酸乳球菌对小鼠免疫保护作用
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摘要
目的
对本课题组前期构建好的H.pylori重组疫苗菌株进行验证、诱导、表达。通过口服灌胃免疫接种BALB/c小鼠,连续免疫一个月后,用H.pylori国际标准株11637进行攻击,检测小鼠胃内H.pylori定植量,评价不同疫苗所产生的免疫应答和免疫保护效果。
方法
1.将过夜培养好的乳酸菌NZ3900/pNZ8110-ureB、NZ3900/pNZ8110-lpp20、 NZ3900/pNZ8110-omp22-hpaA、NZ3900/pNZ8149-ureB、NZ3900/pNZ8110-LysM-hpaA、NZ3900/pNZ8149-SPusp45-ureB nisin诱导表达,离心提取相关蛋白,经SDS-PAGE电泳鉴定重组菌免疫蛋白表达水平,Western-blot鉴定重组蛋白免疫反应性。
2.将过夜培养好的基因工程重组菌TB1(pMAL-c2X-ureB)、TB1(pMAL-c2X-hpaA)、TB1(pMAL-c2X-lpp20)、TB1(pMAL-c2X-omp22)IPTG诱导表达超声破碎提取上清蛋白,经SDS-PAGE验证后,应用直链淀粉亲和层析柱进行纯化,使用BCA蛋白定量试剂盒测定纯化蛋白的浓度。
3.将BALB/c小鼠随机分为9组,口服免疫后,收集一半小鼠的血清和胃液,酶联免疫吸附试验(ELISA)法检测特异性抗体含量水平。剩下小鼠用H.pylori进行灌胃攻击,2周后处死小鼠,取小鼠胃组织做尿素酶半定量实验。
4.统计学分析
应用SPSS17.0进行统计分析。各组资料进行正态性检验后,采用单因素方差分析对各组之间保护率进行评价。
结果
1.SDS-PAGE胶照片显示Nisin诱导重组蛋白Lpp20、UreB、Omp22-HpaA、 LysM-HpaA分别在19kd、66kd、53kd、29kd处显示杂交条带,Western-blot显示各重组蛋白均有良好的免疫原性和免疫反应性。
2.各基因工程重组菌诱导表达经直链淀粉亲和层析柱纯化后,SDS-PAGE显示在相应条带均有杂交条带。
3.BALB/c小鼠口服灌胃后,NZ3900/pNZ8110-LysM-hpaA组血清IgG含量最高,其余各重组菌株组均高于阴性对照组(P<0.05)。H.pylori灌胃攻击后,快速尿素酶检法显示：各重组乳酸菌组OD450值均低于对照组,差异具有统计学意义(P<0.05)。
结论
1.获得了纯度较高H.pylori重组抗原UreB、Lpp20、HpaA、Omp22。
2.经口服灌胃均具有免疫反应性。
3.NZ3900/pNZ8110-LysM-hpaA所引起免疫保护效果最佳
Objectives
In present study, we aimed to induce and express the recombinant vaccine and oral gavage BALB/c mice for a month, then use H.pylori international standard strains11637challenge and test their colonization rate. To evaculate immune response and immune protection effect produced by different vaccine
Method
l.Recombinant vaccine NZ3900/pNZ8110-ureB, NZ3900/pNZ8110-lpp20, NZ3900/pNZ8110-omp22-hpaA,NZ3900/pNZ8149-ureB,NZ3900/pNZ8110-LysM-hpaA,NZ3900/pNZ8149-SPusp45-ureB were cultured overnight and induced by40ng/ml nisin. SDS-PAGE identified recombinant immune protein quantity while Western-blot identified immnological specificity
2. TB1/pMAL-c2X-ureB, TB1/pMAL-c2X-hpaA,TB1/pMAL-c2X-lpp20, TB1/pMAL-c2X-omp22were cultured overnight and induced by0.3mmol/L IPTG Crusing by ultrasound, purifying by Amylose affinity chromato-graphy, and determ-inating protein concentration by BCA
3.The BALB/c mice were randomly divided into9groups, one time pre week for four times. Two week after the last immunization, half of the mice were sacrificed and collected their serum、succus gastricus.Rest of them were attacked with H.pylori, and then they were sacrificed two weeks after challenged, and the stomach was collected for semi-quantitative analysis based on urease test. The immune protective effect of different recombinant L.lactis was evaluate
4. Statistical analysis of data
The data was inputted to computer and the analysis was performed on SPSS17.0.The quantitative variable was analyzed by independent one-way ANOVA. The difference between two groups was analyzed by Bonferroni test.
Results
1.SDS-PAGE gel photo showed that the hybridization band of recombinant proteins of Lpp20, UreB, Omp22-HpaA, LysM-HpaA induced by Nisin were displayed at19kd,66kd,53kd,29kd,respectively, and Western-blot showed the recombinant proteins had good immunogenicity and immune reactivity.
2. TB1/pMAL-c2X-ureB, TB1/pMAL-c2X-hpaA,TB1/pMAL-c2X-lpp20, TB1/pMAL-c2X-omp22were induced by IPTG and purified by Amylose affinity chromatography.
3.Systemic antibody responses induced by recombinant vaccine were higher than pNZ3900/8149group, pNZ3900/8110group and PBS group, While the group of NZ3900/pNZ8110-LysM-hpaA were the highest. After H.pylori challenged, rapid urease test showed all of the recombinant vaccine had a protective effects.
Conclusions
1.Successfully obtained the high purity recombinant H.pylori antigen of Ureb, HpaA, Lpp20, Omp22
2. All of the oral gavage recombinant vaccine have immunogenicity.
3.It discovered that NZ3900/pNZ8110-LysM-hpaA has the best immunorea-ction.
对本课题组前期构建好的H.pylori重组疫苗菌株进行验证、诱导、表达。通过口服灌胃免疫接种BALB/c小鼠,连续免疫一个月后,用H.pylori国际标准株11637进行攻击,检测小鼠胃内H.pylori定植量,评价不同疫苗所产生的免疫应答和免疫保护效果。
方法
1.将过夜培养好的乳酸菌NZ3900/pNZ8110-ureB、NZ3900/pNZ8110-lpp20、 NZ3900/pNZ8110-omp22-hpaA、NZ3900/pNZ8149-ureB、NZ3900/pNZ8110-LysM-hpaA、NZ3900/pNZ8149-SPusp45-ureB nisin诱导表达,离心提取相关蛋白,经SDS-PAGE电泳鉴定重组菌免疫蛋白表达水平,Western-blot鉴定重组蛋白免疫反应性。
2.将过夜培养好的基因工程重组菌TB1(pMAL-c2X-ureB)、TB1(pMAL-c2X-hpaA)、TB1(pMAL-c2X-lpp20)、TB1(pMAL-c2X-omp22)IPTG诱导表达超声破碎提取上清蛋白,经SDS-PAGE验证后,应用直链淀粉亲和层析柱进行纯化,使用BCA蛋白定量试剂盒测定纯化蛋白的浓度。
3.将BALB/c小鼠随机分为9组,口服免疫后,收集一半小鼠的血清和胃液,酶联免疫吸附试验(ELISA)法检测特异性抗体含量水平。剩下小鼠用H.pylori进行灌胃攻击,2周后处死小鼠,取小鼠胃组织做尿素酶半定量实验。
4.统计学分析
应用SPSS17.0进行统计分析。各组资料进行正态性检验后,采用单因素方差分析对各组之间保护率进行评价。
结果
1.SDS-PAGE胶照片显示Nisin诱导重组蛋白Lpp20、UreB、Omp22-HpaA、 LysM-HpaA分别在19kd、66kd、53kd、29kd处显示杂交条带,Western-blot显示各重组蛋白均有良好的免疫原性和免疫反应性。
2.各基因工程重组菌诱导表达经直链淀粉亲和层析柱纯化后,SDS-PAGE显示在相应条带均有杂交条带。
3.BALB/c小鼠口服灌胃后,NZ3900/pNZ8110-LysM-hpaA组血清IgG含量最高,其余各重组菌株组均高于阴性对照组(P<0.05)。H.pylori灌胃攻击后,快速尿素酶检法显示：各重组乳酸菌组OD450值均低于对照组,差异具有统计学意义(P<0.05)。
结论
1.获得了纯度较高H.pylori重组抗原UreB、Lpp20、HpaA、Omp22。
2.经口服灌胃均具有免疫反应性。
3.NZ3900/pNZ8110-LysM-hpaA所引起免疫保护效果最佳
Objectives
In present study, we aimed to induce and express the recombinant vaccine and oral gavage BALB/c mice for a month, then use H.pylori international standard strains11637challenge and test their colonization rate. To evaculate immune response and immune protection effect produced by different vaccine
Method
l.Recombinant vaccine NZ3900/pNZ8110-ureB, NZ3900/pNZ8110-lpp20, NZ3900/pNZ8110-omp22-hpaA,NZ3900/pNZ8149-ureB,NZ3900/pNZ8110-LysM-hpaA,NZ3900/pNZ8149-SPusp45-ureB were cultured overnight and induced by40ng/ml nisin. SDS-PAGE identified recombinant immune protein quantity while Western-blot identified immnological specificity
2. TB1/pMAL-c2X-ureB, TB1/pMAL-c2X-hpaA,TB1/pMAL-c2X-lpp20, TB1/pMAL-c2X-omp22were cultured overnight and induced by0.3mmol/L IPTG Crusing by ultrasound, purifying by Amylose affinity chromato-graphy, and determ-inating protein concentration by BCA
3.The BALB/c mice were randomly divided into9groups, one time pre week for four times. Two week after the last immunization, half of the mice were sacrificed and collected their serum、succus gastricus.Rest of them were attacked with H.pylori, and then they were sacrificed two weeks after challenged, and the stomach was collected for semi-quantitative analysis based on urease test. The immune protective effect of different recombinant L.lactis was evaluate
4. Statistical analysis of data
The data was inputted to computer and the analysis was performed on SPSS17.0.The quantitative variable was analyzed by independent one-way ANOVA. The difference between two groups was analyzed by Bonferroni test.
Results
1.SDS-PAGE gel photo showed that the hybridization band of recombinant proteins of Lpp20, UreB, Omp22-HpaA, LysM-HpaA induced by Nisin were displayed at19kd,66kd,53kd,29kd,respectively, and Western-blot showed the recombinant proteins had good immunogenicity and immune reactivity.
2. TB1/pMAL-c2X-ureB, TB1/pMAL-c2X-hpaA,TB1/pMAL-c2X-lpp20, TB1/pMAL-c2X-omp22were induced by IPTG and purified by Amylose affinity chromatography.
3.Systemic antibody responses induced by recombinant vaccine were higher than pNZ3900/8149group, pNZ3900/8110group and PBS group, While the group of NZ3900/pNZ8110-LysM-hpaA were the highest. After H.pylori challenged, rapid urease test showed all of the recombinant vaccine had a protective effects.
Conclusions
1.Successfully obtained the high purity recombinant H.pylori antigen of Ureb, HpaA, Lpp20, Omp22
2. All of the oral gavage recombinant vaccine have immunogenicity.
3.It discovered that NZ3900/pNZ8110-LysM-hpaA has the best immunorea-ction.
引文
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