弓形虫表面抗原SAG3单克隆抗体的制备及应用研究
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摘要
本研究通过原核表达去信号肽的RH株弓形虫表面抗原SAG3蛋白，并制备SAG3的单克隆抗体，建立间接ELISA法和双抗夹心ELISA方法，并进行初步应用。
SAG3去信号肽基因的克隆和原核表达提取RH株弓形虫的总RNA，反转录为cDNA为模板， PCR扩增SAG3基因。构建其原核表达载体pET-28a(+)-SAG3，并转化至E.coli BL21(DE3)中，IPTG诱导表达， SDS-PAGE检测蛋白表达情况，western blotting检测其反应性。结果显示，成功扩增了去信号肽的SAG3基因，测序结果与GenBank公布的弓形虫RH株SAG3基因序列同源性为100%。SDS-PAGE表明成功表达了去信号肽的SAG3蛋白，分子量大小为38Kda，western blotting结果显示重组蛋白能够被鼠抗弓形虫血清识别，具有很好的反应原性。
刚地弓形虫RH株SAG3蛋白抗体检测的间接ELISA方法建立利用Ni-NTA亲和层析柱对SAG3蛋白进行纯化，并以纯化的SAG3蛋白作为抗原，建立弓形虫RH株蛋白抗体检测的ELISA方法。结果显示，经Ni-NTA亲和层析柱纯化后，SDS-PAGE分析在38kDa处有一条单一的目的蛋白带，成功纯化SAG3蛋白。建立的ELISA方法的最佳工作条件为：最佳封闭液是5%脱脂奶粉的PBST溶液，最佳检测条件是抗原包被浓度0.25μg/孔、被检血清稀释度1∶400、羊抗鼠二抗稀释倍数1:3000。建立的ELISA方法具有较高的敏感性，此方法与鼠抗C. andersoni阳性血清、鼠抗C. parvum阳性血清鼠、抗G. lamblia阳性血清、鼠抗E. tenella阳性血清和鼠抗Neosporacaninum阳性血清均无交叉反应，具有较强的特异性。用所建立的SAG3-ELISA方法检测了10份阳性血清，符合率100%。检测了24份普通级小鼠血清进行检测，阳性率为20.8%。
弓形虫表面蛋白SAG3的单克隆抗体的制备及纯化以纯化的SAG3为免疫原，免疫小鼠，进行融合，制备抗SAG3的单克隆抗体。利用建立的SAG3-ELISA方法筛选出了2株能够稳定分泌抗体的细胞株1A1和3E5。腹水效价约为1:102400，单克隆抗体亚类鉴定1A1为IgG2a，3E5为IgM。Western blotting结果表明，1A1和3E5单克隆抗体均可识别重组SAG3蛋白。SDS-PAGE结果表明成功纯化了单抗腹水，能够清晰的观察到轻链和重链两条带。
双抗夹心ELISA检测方法的建立以纯化的1A1单克隆抗体作为捕获抗体，以HRP标记的3E5单克隆抗体作为检测抗体，建立弓形虫的双抗夹心ELISA方法。所建立的夹心ELISA方法的最佳检测条件分别为：包被抗体1:100，HRP标记抗体1:400，被检血清最佳稀释度为1:10，最佳封闭剂为1%BSA。经验证此方法与犬新孢子虫阳性血清没有交叉反应，特异性较强。批内和批间重复试验表明建立的ELISA方法具有重复性。利用建立的ELISA方法对人工感染弓形虫的小鼠阳性血清（小鼠腹水经检测含有弓形虫虫体），和无弓形虫的SPF小鼠血清进行检测，结果符合率为100%。应用已建立的双抗夹心ELISA方法对85份弓形虫感染情况不明确的牛血清，63份鸡血清，58份犬血清和67份猪血清进行检测，发现阳性结果率分别为：7.06%，12.70%，10.34%和28.36%。本研究的检测方法要求的被检样品为血清，需要量少，易于采取，处理简单，特异性好，操作方便，利于推广，有一定的应用前景。
The research was conducted to prokaryotic express the SAG3gene containing nosignal peptide of Toxoplasma gondii(T.gondii), and then preparation of the SAG3monoclonal antibody which were used for establishing the double-antibody sandwichELISA.
Clone, express and identify the SAG3gene containing no signal peptide ofT.gondii Total RNA was extracted from T. gondii and SAG3gene containing nosignal peptide was amplified by RT-PCR, then sub-cloned into the pET-28a（+）. Therecombinant plasmid pET-28a（+）-SAG3was transformed into E. coli BL21（DE3）and induced with IPTG. The expression of pET-28a-SAG3was induced by IPTG in E.coli BL21（DE3）system; then the fusion protein was identified by SDS-PAGE andWestern blotting. SDS-PAGE result showed that the recombinant protein（Mr38000）was expressed in the form of inclusion body and could specially recognize bypolyclonal antibody against the SAG3of T. gondii.
Develop an indirect ELISA which used for detecting SAG3antibodyCheckerboard titration was used to determine the optimal conditions of the indirectELISA. The optimal antigen concentration for coating was0.25μg/hole, and theoptimal dilutions of the sera of T. gondii and enzyme-labeled the second antibodywere1:400and1:3000respectively, blocking agent was the PBST solution of5%nonfat dry milk by chessboard titration. The developed indirect ELISA had no crossreaction with positive serums which mentioned in the following brackets (Neosporacaninum, G. lamblia, C. andersoni, E. tenella and C. parvum). It showed highsensitivity of1:1600and strong specificity.10positive samples and24unknownsamples were detected by the indirect ELISA, the positive rate are100%and20.8%respectively.
Preparation and purification of monoclonal antibodies of SAG3proteinRecombinant protein SAG3was purified as immunogen for preparing the monoclonal antibody. Two cell lines (1A1and3E5) were screened by indirect SAG3-ELISA. Bothtiters about1:102400. The immunoglobulin subclass of the1A1and3E5are IgG2aandIgM. Western blotting showed that SAG3protein could specially recognize by1A1and3E5. The light chain and the heavy chain of the antibody could be distinguishedwell by SDS-PAGE means that antibodies were purified successfully.
Establishment of double monoclonal antibody sandwich ELISA Purified1A1monoclonal antibody as the capture antibody, HRP-labeled3E5monoclonalantibodies as the detection antibody were used for establishing double monoclonalantibody sandwich ELISA of T. gondii. The optimum conditions established by thesandwich ELISA method was: coated antibody1:100, HRP labeled antibody1:400,test serum dilution of1:10, the best blocking agent for1%BSA. The developedsandwich ELISA had no cross reaction with N. caninum positive serum. The intra andbetween repeated experiments showed that the ELISA has repeatability. The positivesamples and negative samples were detected by this way, the coincidence was100%.85bovine sera samples,63chicken sera samples,58dog sera samples and67pig serasamples were detected by sandwich ELISA, the positive rate are7.06%,12.70%,10.34%and28.36%. The developed sandwich ELISA requires that the seizure samplefor serum, easy to collect, easy to prepare, good specificity, easy to operate,conducive to the promotion and has well application prospects.
SAG3去信号肽基因的克隆和原核表达提取RH株弓形虫的总RNA，反转录为cDNA为模板， PCR扩增SAG3基因。构建其原核表达载体pET-28a(+)-SAG3，并转化至E.coli BL21(DE3)中，IPTG诱导表达， SDS-PAGE检测蛋白表达情况，western blotting检测其反应性。结果显示，成功扩增了去信号肽的SAG3基因，测序结果与GenBank公布的弓形虫RH株SAG3基因序列同源性为100%。SDS-PAGE表明成功表达了去信号肽的SAG3蛋白，分子量大小为38Kda，western blotting结果显示重组蛋白能够被鼠抗弓形虫血清识别，具有很好的反应原性。
刚地弓形虫RH株SAG3蛋白抗体检测的间接ELISA方法建立利用Ni-NTA亲和层析柱对SAG3蛋白进行纯化，并以纯化的SAG3蛋白作为抗原，建立弓形虫RH株蛋白抗体检测的ELISA方法。结果显示，经Ni-NTA亲和层析柱纯化后，SDS-PAGE分析在38kDa处有一条单一的目的蛋白带，成功纯化SAG3蛋白。建立的ELISA方法的最佳工作条件为：最佳封闭液是5%脱脂奶粉的PBST溶液，最佳检测条件是抗原包被浓度0.25μg/孔、被检血清稀释度1∶400、羊抗鼠二抗稀释倍数1:3000。建立的ELISA方法具有较高的敏感性，此方法与鼠抗C. andersoni阳性血清、鼠抗C. parvum阳性血清鼠、抗G. lamblia阳性血清、鼠抗E. tenella阳性血清和鼠抗Neosporacaninum阳性血清均无交叉反应，具有较强的特异性。用所建立的SAG3-ELISA方法检测了10份阳性血清，符合率100%。检测了24份普通级小鼠血清进行检测，阳性率为20.8%。
弓形虫表面蛋白SAG3的单克隆抗体的制备及纯化以纯化的SAG3为免疫原，免疫小鼠，进行融合，制备抗SAG3的单克隆抗体。利用建立的SAG3-ELISA方法筛选出了2株能够稳定分泌抗体的细胞株1A1和3E5。腹水效价约为1:102400，单克隆抗体亚类鉴定1A1为IgG2a，3E5为IgM。Western blotting结果表明，1A1和3E5单克隆抗体均可识别重组SAG3蛋白。SDS-PAGE结果表明成功纯化了单抗腹水，能够清晰的观察到轻链和重链两条带。
双抗夹心ELISA检测方法的建立以纯化的1A1单克隆抗体作为捕获抗体，以HRP标记的3E5单克隆抗体作为检测抗体，建立弓形虫的双抗夹心ELISA方法。所建立的夹心ELISA方法的最佳检测条件分别为：包被抗体1:100，HRP标记抗体1:400，被检血清最佳稀释度为1:10，最佳封闭剂为1%BSA。经验证此方法与犬新孢子虫阳性血清没有交叉反应，特异性较强。批内和批间重复试验表明建立的ELISA方法具有重复性。利用建立的ELISA方法对人工感染弓形虫的小鼠阳性血清（小鼠腹水经检测含有弓形虫虫体），和无弓形虫的SPF小鼠血清进行检测，结果符合率为100%。应用已建立的双抗夹心ELISA方法对85份弓形虫感染情况不明确的牛血清，63份鸡血清，58份犬血清和67份猪血清进行检测，发现阳性结果率分别为：7.06%，12.70%，10.34%和28.36%。本研究的检测方法要求的被检样品为血清，需要量少，易于采取，处理简单，特异性好，操作方便，利于推广，有一定的应用前景。
The research was conducted to prokaryotic express the SAG3gene containing nosignal peptide of Toxoplasma gondii(T.gondii), and then preparation of the SAG3monoclonal antibody which were used for establishing the double-antibody sandwichELISA.
Clone, express and identify the SAG3gene containing no signal peptide ofT.gondii Total RNA was extracted from T. gondii and SAG3gene containing nosignal peptide was amplified by RT-PCR, then sub-cloned into the pET-28a（+）. Therecombinant plasmid pET-28a（+）-SAG3was transformed into E. coli BL21（DE3）and induced with IPTG. The expression of pET-28a-SAG3was induced by IPTG in E.coli BL21（DE3）system; then the fusion protein was identified by SDS-PAGE andWestern blotting. SDS-PAGE result showed that the recombinant protein（Mr38000）was expressed in the form of inclusion body and could specially recognize bypolyclonal antibody against the SAG3of T. gondii.
Develop an indirect ELISA which used for detecting SAG3antibodyCheckerboard titration was used to determine the optimal conditions of the indirectELISA. The optimal antigen concentration for coating was0.25μg/hole, and theoptimal dilutions of the sera of T. gondii and enzyme-labeled the second antibodywere1:400and1:3000respectively, blocking agent was the PBST solution of5%nonfat dry milk by chessboard titration. The developed indirect ELISA had no crossreaction with positive serums which mentioned in the following brackets (Neosporacaninum, G. lamblia, C. andersoni, E. tenella and C. parvum). It showed highsensitivity of1:1600and strong specificity.10positive samples and24unknownsamples were detected by the indirect ELISA, the positive rate are100%and20.8%respectively.
Preparation and purification of monoclonal antibodies of SAG3proteinRecombinant protein SAG3was purified as immunogen for preparing the monoclonal antibody. Two cell lines (1A1and3E5) were screened by indirect SAG3-ELISA. Bothtiters about1:102400. The immunoglobulin subclass of the1A1and3E5are IgG2aandIgM. Western blotting showed that SAG3protein could specially recognize by1A1and3E5. The light chain and the heavy chain of the antibody could be distinguishedwell by SDS-PAGE means that antibodies were purified successfully.
Establishment of double monoclonal antibody sandwich ELISA Purified1A1monoclonal antibody as the capture antibody, HRP-labeled3E5monoclonalantibodies as the detection antibody were used for establishing double monoclonalantibody sandwich ELISA of T. gondii. The optimum conditions established by thesandwich ELISA method was: coated antibody1:100, HRP labeled antibody1:400,test serum dilution of1:10, the best blocking agent for1%BSA. The developedsandwich ELISA had no cross reaction with N. caninum positive serum. The intra andbetween repeated experiments showed that the ELISA has repeatability. The positivesamples and negative samples were detected by this way, the coincidence was100%.85bovine sera samples,63chicken sera samples,58dog sera samples and67pig serasamples were detected by sandwich ELISA, the positive rate are7.06%,12.70%,10.34%and28.36%. The developed sandwich ELISA requires that the seizure samplefor serum, easy to collect, easy to prepare, good specificity, easy to operate,conducive to the promotion and has well application prospects.
引文
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