副结核分枝杆菌hsp65基因的克隆、表达与免疫研究
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摘要
副结核病(Paratuberculosis)是由副结核分枝杆菌即禽分枝杆菌副结核亚种(Mycobacterium avium subsp．Paratuberculosis，MAP)引起的一种以反刍动物为主要宿主的慢性增生性、顽固性肠炎和进行性消瘦为特征的传染病，也称Johne’s病。该病不仅使病畜的饲料报酬降低，产奶量和繁殖力下降，造成巨大的经济损失，而且还与人类的克隆氏(Crohn’s)病存在潜在联系，因此，愈来愈受到世界各国的广泛关注。目前，该病尚无经济有效的治疗药物，控制该病的主要措施是加强饲养管理和消除传染源，即以变态反应、ELISA、病原分离鉴定等方法进行检疫，对检出的阳性牛隔离与淘汰。此外，也可采用预防接种的方法来控制该病，即将MAP灭活或致弱后制成疫苗进行免疫，接种疫苗不仅使该病的临床型病例减少90％，而且减少了亚临床感染动物的数量和组织学或细菌学检测阳性的病例。但是，菌苗接种后会干扰该病和结核病的变态反应和血清学检测，许多国家已经禁止使用接种菌苗来控制副结核病。因此，研究开发副结核病的新型疫苗势在必行。
热休克蛋白(HSPs)是生物体受到物理、化学、生物、精神等刺激时发生应激反应而合成的高度保守的蛋白质。根据分子量，将主要的热休克蛋白分为5个家族：大分子量家族、HSP90家族、HSP70家族、HSP60家族和小分子量家族。Hsp60作为一种分子伴侣，能协助变性、不可溶的凝聚蛋白重新恢复天然构象，在许多病原体传染过程中是免疫优势抗原。hsp65基因又名groEL2基因，其编码的蛋白是HSP60家族成员，不仅可作为分枝杆菌的主要保护性抗原，还具有帮助树突状细胞递呈抗原等功能。Hsp10(GroES)作为辅分子伴侣，在GroLS指导蛋白质折叠过程中具有辅助其活性的作用，同时作为一种有效的T细胞抗原，能刺激机体产生特异性细胞免疫应答，使外周血单核细胞出现增殖反应并产生IFN-γ，是制备新型疫苗的候选抗原。
为了研发预防副结核病的新型疫苗尤其是DNA疫苗及相关蛋白功能，本研究选择了MAP的主要保护性抗原Hsp65蛋白，以副结核分枝杆菌C-2株染色体DNA为模板，以hsp65基因的特异性引物进行PCR扩增，获得了1 626bp的hsp65基因，通过T-A克隆技术，将PCR产物克隆至pGEM-T Vector中，以质粒大小、酶切分析、PCR扩增及序列分析鉴定重组克隆，成功地构建出克隆质粒pGEM-T-hsp65，以DNASTAR软件分析了所克隆基因的核苷酸序列和推导的氨基酸序列，结果表明，所获得的hsp65基因与GenBank中MAPK-10株该基因核苷酸大小完全一致，两者核苷酸序列的同源性为99．1％，氨基酸序列的同源性为99．3％，表明该基因在副结核分枝杆菌中高度保守。进一步将pGEM-T-hsp65中的hsp65基因酶切、纯化后亚克隆至pET-32a(+)原核表达系统中，构建了高效原核表达质粒pET-32a-hsp65，在与之相匹配的E．coli BL21(DE3)表达菌株中，该质粒经IPTG诱导获得了76Ku的融合蛋白。经免疫印迹分析证实，该融合蛋白具有与副结核分枝杆菌多克隆抗体发生反应的特性。
在上述研究的基础上，为研究开发MAP主要保护性基因hsp65的DNA疫苗，将克隆质粒pGEM-T-hsp65中的hsp65基因酶切、纯化后亚克隆至真核表达载体pVAX1中，成功构建了真核表达重组质粒pVAX1-hsp65，并以阳离子聚合物基因转染试剂将真核表达重组质粒转染至BHK-21细胞中，通过荧光抗体和RT-PCR技术证实hsp65基因可以在哺乳动物细胞中表达，同时将pGEM-T-hsp65中的hsp65基因酶切、纯化后亚克隆至pVAX1-hsp10中，成功构建了真核表达重组质粒pVAX1-hsp65-10。
以pVAX1-hsp65和pVAX1-hsp65-10重组质粒免疫BALB／c小鼠，同时设pVAX1、生理盐水为对照组。特异性抗体检测结果显示，免疫小鼠体内分别产生了针对Hsp65的特异性抗体，且二价基因免疫组的抗体水平高于单价基因。淋巴细胞转化试验结果显示，pVAX1-hsp65和pVAX1-hsp65-10免疫组的淋巴细胞增殖活性高于生理盐水对照组，而pVAX1-hsp65和pVAX1-hsp65-10实验组之间差异不显著(P＞0．05)。CD3~+、CD4~+、CD8~+T细胞检测结果显示，pVAX1-hsp65和pVAX1-hsp65-10免疫组CD8~+T细胞水平高于对照组，尚未达到统计学的显著水平(P＞0．05)，但也表明实验组产生了较高的以MHCⅠ类分子递呈的细胞免疫应答，pVAX1-hsp65免疫组的CD4~+、CD3~+T细胞数量明显高于其它组。重组质粒pVAX1-hsp65-10免疫组小鼠的IFN-γ水平明显高于对照组，pVAX1-hsp65免疫组的小鼠IFN-γ水平略高于对照组，均未达到统计学上的显著水平(P＞0．05)，但结果显示，重组质粒pVAX1-hsp65和pVAX1-hsp65-10均使免疫小鼠产生了细胞免疫，而且二价基因的免疫效果优于单价基因。
以pVAX1-hsp65和pVAX1-hsp65-10免疫豚鼠，同时设pVAX1和副结核分枝杆菌超声抗原对照组。禽结核杆菌PPD皮试结果显示，pVAX1-hsp65和pVAX1-hsp65-10免疫组与副结核分枝杆菌超声抗原免疫组差异极显著(P＜0．01)，表明Hsp65和Hsp10不干扰变态反应检测。
Paratuberculosis disease caused by Mycobacterium avium subsp.Paratuberculosis (MAP,Mycobacterium paratuberculosis) induce a series of characteristics as chronic hyperplastic enteritis andprogressing extenuation in ruminants also called Johne's disease.It causes the cut down of foragereward,milk secretion and productivity in animals and result in great loss to animal husbandry.Thisdisease has received extensive attention globally for its potential relation to human Crohn's disease.Atpresent,there is no effective drug to treat this disease and for eradicating source of infection andreinforce breeding management are the major preventive measures including allergy,ELISA,separationand identification of pathogen.Then isolate or reject the positive cattle.In addition,vaccination withinactivated or attenuated MAP also can be used to control the disease.Although the cut down of milkproduction can't be prevented by immunization but the clinical cases can be reduced 90% and theamount of sub clinical infectious animals and positive cases detected by histology or bacteriology alsowere reduced.But that immunized with whole strain vaccine will interfer the allergy and serologicdetection so this method has been forbidden in many countries.Therefore the exploitation of newgeneration vaccine for paratuberculosis disease is imperative.
Heat shock proteins (HSPs) are highly conservative protein synthetized by organism whenstimulated by physical,chemical,biological and mental factors.Main HSPs can be divided into 5families on account of molecular weight including macromolecule weight family,HSP90 family,HSP70 family,HSP60 family and micromolecule weight family.HSP60 as a kind of molecularchaperones is a kind of immunodominant antigen in the infectious process of many pathogens and it canassist recovery of native conformation of degenerated and indissoluble agglomeration protein.Hsp65gene also called groEL2 gene and its codogenic protein is HSP60 family.This protein not only is themajor protective antigen but also has function of submitting antigen assisting dendritic cell.Hspl0(GroES) as a kind of assisting molecular chaperones can assist the protein folding directed byGroLS.As a kind of efficient T cell antigen,it can stimulate the organism generate specific cellullarimmunologic response and induce the generation of IFN-γby proliferation of peripheral bloodmonouclear cells in PPD dermal test positive cases.It also can be used as alternative antigen of newgeneration vaccine.In this experiment,we screen the major protective antigen hsp65 gene of MAP in order to developnew vaccine especially the DNA vaccine for the prevention of paratuberculosis disease.The hsp65 genewas amplified from MAP C-2 chromosomal DNA by using the PCR technique.We gained a hsp65 gene of 1 626bp.Then PCR product was cloned into pGEM-T vector by T-A clone technique and therecombinant clone was identified by plasmid size,enzyme digestion and PCR identification.The cloneplasmid of pGEM-T- hsp65 was successfully constructed.The nucleotide sequence and deduced aminoacid sequence ofclone gene was analyzed by DNASTAR software.The result indicated that the size ofhsp65 gene consist with M.paratuberculosis K-10 strain in GenBank and the sequential homogeneityreached 99.1%,the amino acid homogeneity reached 99.3%.The preceding analysis indicated that thehsp65 gene was very conservative in M.paratuberculosis.The hsp65 gene that was digested withenzyme from pGEM-T- hsp65,purified and then subcloned into a pET-32a(+) procaryotic expressionsystem,then the procaryotic expression plasmid pET-32a- hsp65 was constructed successfully.Theplasmid was transformed into E.coli BL21(DE3) and induced by IPTG.We gained a 76Ku fusionprotein.The expression protein was analyzed using Western-blot,which proved that it had the antigenicactivity of Mycobacterium avium subsp.Paratuberculosis.
Base on above study,in order to study DNA vaccine of hsp65 gene the major protective gene ofMAP.Hsp65 gene from recombinant plasmid pGEM-T-hsp65 was subcloned into the eukaryoticexpression vector pVAX1,then the eukaryotic expression plasmids pVAX1-hsp65 were successfullyconstructed.Transfect BHK-21 cells with the constructed recombinant plasmid pVAXI-hsp65 bycationic polymerization gene transfection reagent and observe the expression in mammalian cells ofhsp65 gene by immunofluorescence and RT-PCR.Meanwhile hsp65 gene from recombinant plasmidpGEM-T- hsp65 was subcloned into pVAX1-hsp10 and the eukaryotic expression recombinant plasmidpVAX1- hsp65-10 was constructed successfully.
BALB/c mice was vaccinated with pVAX1-hsp65 and pVAX1-hsp65-10 recombinant plasmid,moreover,pVAX1 and sodium chloride as control.Detection of specific antibody shows that and thereis a generation of specific antibody against hsp65 and the antibody titer in bivalent gene group is higherthan single gene group.Lymphocyte transformation test show that cell proliferation activity in pVAX1-hsp65 and pVAX1- hsp65-10 group was higher than sodium chloride control group and there is nosignificant difference between pVAX1- hsp65 and pVAX1- hsp65-10 group (P＞0.05).CD3~+T、CD4~+T and CD8~+T ceils determination results demonstrated that CD8~+T cells in pVAX1-hsp65 andpVAX1- hsp65-10 group were more than the control group with non-significant difference (P＞0.05 ).This also shows a MHCⅠtype cell immune response in experimental group.The amount.of CD4~+Tand CD3~+T cells in pVAX1-hsp65 group is significantly higher than the other groups.The IFN-γlevelin pVAX1- hsp65 and pVAX1- hsp65-10 group were higher than control group,but not yet reached astatistically significance (P＞0.05).However the result show that recombinant plasmids immunizationstrengthened the cell immunity of mice,and bivalent gene group is higher than single gene group.
Cavia cobaya was vaccinated with pVAX1- hsp65 and pVAX1- hsp65-10 recombinant plasmid,moreover,pVAX 1 and supersonic antigen of MAP as control.The allergy quarantine with avian bacillustuberculosis PPD indicated that there is significantly difference between the pVAXl-hsp65,pVAX1-hsp65-10 groups and supersonic antigen of MAP group (P＜0.01).This indicates that the Hsp65 andHsp 10 does not interfere with detection of Paratuberculosis allergy.
热休克蛋白(HSPs)是生物体受到物理、化学、生物、精神等刺激时发生应激反应而合成的高度保守的蛋白质。根据分子量，将主要的热休克蛋白分为5个家族：大分子量家族、HSP90家族、HSP70家族、HSP60家族和小分子量家族。Hsp60作为一种分子伴侣，能协助变性、不可溶的凝聚蛋白重新恢复天然构象，在许多病原体传染过程中是免疫优势抗原。hsp65基因又名groEL2基因，其编码的蛋白是HSP60家族成员，不仅可作为分枝杆菌的主要保护性抗原，还具有帮助树突状细胞递呈抗原等功能。Hsp10(GroES)作为辅分子伴侣，在GroLS指导蛋白质折叠过程中具有辅助其活性的作用，同时作为一种有效的T细胞抗原，能刺激机体产生特异性细胞免疫应答，使外周血单核细胞出现增殖反应并产生IFN-γ，是制备新型疫苗的候选抗原。
为了研发预防副结核病的新型疫苗尤其是DNA疫苗及相关蛋白功能，本研究选择了MAP的主要保护性抗原Hsp65蛋白，以副结核分枝杆菌C-2株染色体DNA为模板，以hsp65基因的特异性引物进行PCR扩增，获得了1 626bp的hsp65基因，通过T-A克隆技术，将PCR产物克隆至pGEM-T Vector中，以质粒大小、酶切分析、PCR扩增及序列分析鉴定重组克隆，成功地构建出克隆质粒pGEM-T-hsp65，以DNASTAR软件分析了所克隆基因的核苷酸序列和推导的氨基酸序列，结果表明，所获得的hsp65基因与GenBank中MAPK-10株该基因核苷酸大小完全一致，两者核苷酸序列的同源性为99．1％，氨基酸序列的同源性为99．3％，表明该基因在副结核分枝杆菌中高度保守。进一步将pGEM-T-hsp65中的hsp65基因酶切、纯化后亚克隆至pET-32a(+)原核表达系统中，构建了高效原核表达质粒pET-32a-hsp65，在与之相匹配的E．coli BL21(DE3)表达菌株中，该质粒经IPTG诱导获得了76Ku的融合蛋白。经免疫印迹分析证实，该融合蛋白具有与副结核分枝杆菌多克隆抗体发生反应的特性。
在上述研究的基础上，为研究开发MAP主要保护性基因hsp65的DNA疫苗，将克隆质粒pGEM-T-hsp65中的hsp65基因酶切、纯化后亚克隆至真核表达载体pVAX1中，成功构建了真核表达重组质粒pVAX1-hsp65，并以阳离子聚合物基因转染试剂将真核表达重组质粒转染至BHK-21细胞中，通过荧光抗体和RT-PCR技术证实hsp65基因可以在哺乳动物细胞中表达，同时将pGEM-T-hsp65中的hsp65基因酶切、纯化后亚克隆至pVAX1-hsp10中，成功构建了真核表达重组质粒pVAX1-hsp65-10。
以pVAX1-hsp65和pVAX1-hsp65-10重组质粒免疫BALB／c小鼠，同时设pVAX1、生理盐水为对照组。特异性抗体检测结果显示，免疫小鼠体内分别产生了针对Hsp65的特异性抗体，且二价基因免疫组的抗体水平高于单价基因。淋巴细胞转化试验结果显示，pVAX1-hsp65和pVAX1-hsp65-10免疫组的淋巴细胞增殖活性高于生理盐水对照组，而pVAX1-hsp65和pVAX1-hsp65-10实验组之间差异不显著(P＞0．05)。CD3~+、CD4~+、CD8~+T细胞检测结果显示，pVAX1-hsp65和pVAX1-hsp65-10免疫组CD8~+T细胞水平高于对照组，尚未达到统计学的显著水平(P＞0．05)，但也表明实验组产生了较高的以MHCⅠ类分子递呈的细胞免疫应答，pVAX1-hsp65免疫组的CD4~+、CD3~+T细胞数量明显高于其它组。重组质粒pVAX1-hsp65-10免疫组小鼠的IFN-γ水平明显高于对照组，pVAX1-hsp65免疫组的小鼠IFN-γ水平略高于对照组，均未达到统计学上的显著水平(P＞0．05)，但结果显示，重组质粒pVAX1-hsp65和pVAX1-hsp65-10均使免疫小鼠产生了细胞免疫，而且二价基因的免疫效果优于单价基因。
以pVAX1-hsp65和pVAX1-hsp65-10免疫豚鼠，同时设pVAX1和副结核分枝杆菌超声抗原对照组。禽结核杆菌PPD皮试结果显示，pVAX1-hsp65和pVAX1-hsp65-10免疫组与副结核分枝杆菌超声抗原免疫组差异极显著(P＜0．01)，表明Hsp65和Hsp10不干扰变态反应检测。
Paratuberculosis disease caused by Mycobacterium avium subsp.Paratuberculosis (MAP,Mycobacterium paratuberculosis) induce a series of characteristics as chronic hyperplastic enteritis andprogressing extenuation in ruminants also called Johne's disease.It causes the cut down of foragereward,milk secretion and productivity in animals and result in great loss to animal husbandry.Thisdisease has received extensive attention globally for its potential relation to human Crohn's disease.Atpresent,there is no effective drug to treat this disease and for eradicating source of infection andreinforce breeding management are the major preventive measures including allergy,ELISA,separationand identification of pathogen.Then isolate or reject the positive cattle.In addition,vaccination withinactivated or attenuated MAP also can be used to control the disease.Although the cut down of milkproduction can't be prevented by immunization but the clinical cases can be reduced 90% and theamount of sub clinical infectious animals and positive cases detected by histology or bacteriology alsowere reduced.But that immunized with whole strain vaccine will interfer the allergy and serologicdetection so this method has been forbidden in many countries.Therefore the exploitation of newgeneration vaccine for paratuberculosis disease is imperative.
Heat shock proteins (HSPs) are highly conservative protein synthetized by organism whenstimulated by physical,chemical,biological and mental factors.Main HSPs can be divided into 5families on account of molecular weight including macromolecule weight family,HSP90 family,HSP70 family,HSP60 family and micromolecule weight family.HSP60 as a kind of molecularchaperones is a kind of immunodominant antigen in the infectious process of many pathogens and it canassist recovery of native conformation of degenerated and indissoluble agglomeration protein.Hsp65gene also called groEL2 gene and its codogenic protein is HSP60 family.This protein not only is themajor protective antigen but also has function of submitting antigen assisting dendritic cell.Hspl0(GroES) as a kind of assisting molecular chaperones can assist the protein folding directed byGroLS.As a kind of efficient T cell antigen,it can stimulate the organism generate specific cellullarimmunologic response and induce the generation of IFN-γby proliferation of peripheral bloodmonouclear cells in PPD dermal test positive cases.It also can be used as alternative antigen of newgeneration vaccine.In this experiment,we screen the major protective antigen hsp65 gene of MAP in order to developnew vaccine especially the DNA vaccine for the prevention of paratuberculosis disease.The hsp65 genewas amplified from MAP C-2 chromosomal DNA by using the PCR technique.We gained a hsp65 gene of 1 626bp.Then PCR product was cloned into pGEM-T vector by T-A clone technique and therecombinant clone was identified by plasmid size,enzyme digestion and PCR identification.The cloneplasmid of pGEM-T- hsp65 was successfully constructed.The nucleotide sequence and deduced aminoacid sequence ofclone gene was analyzed by DNASTAR software.The result indicated that the size ofhsp65 gene consist with M.paratuberculosis K-10 strain in GenBank and the sequential homogeneityreached 99.1%,the amino acid homogeneity reached 99.3%.The preceding analysis indicated that thehsp65 gene was very conservative in M.paratuberculosis.The hsp65 gene that was digested withenzyme from pGEM-T- hsp65,purified and then subcloned into a pET-32a(+) procaryotic expressionsystem,then the procaryotic expression plasmid pET-32a- hsp65 was constructed successfully.Theplasmid was transformed into E.coli BL21(DE3) and induced by IPTG.We gained a 76Ku fusionprotein.The expression protein was analyzed using Western-blot,which proved that it had the antigenicactivity of Mycobacterium avium subsp.Paratuberculosis.
Base on above study,in order to study DNA vaccine of hsp65 gene the major protective gene ofMAP.Hsp65 gene from recombinant plasmid pGEM-T-hsp65 was subcloned into the eukaryoticexpression vector pVAX1,then the eukaryotic expression plasmids pVAX1-hsp65 were successfullyconstructed.Transfect BHK-21 cells with the constructed recombinant plasmid pVAXI-hsp65 bycationic polymerization gene transfection reagent and observe the expression in mammalian cells ofhsp65 gene by immunofluorescence and RT-PCR.Meanwhile hsp65 gene from recombinant plasmidpGEM-T- hsp65 was subcloned into pVAX1-hsp10 and the eukaryotic expression recombinant plasmidpVAX1- hsp65-10 was constructed successfully.
BALB/c mice was vaccinated with pVAX1-hsp65 and pVAX1-hsp65-10 recombinant plasmid,moreover,pVAX1 and sodium chloride as control.Detection of specific antibody shows that and thereis a generation of specific antibody against hsp65 and the antibody titer in bivalent gene group is higherthan single gene group.Lymphocyte transformation test show that cell proliferation activity in pVAX1-hsp65 and pVAX1- hsp65-10 group was higher than sodium chloride control group and there is nosignificant difference between pVAX1- hsp65 and pVAX1- hsp65-10 group (P＞0.05).CD3~+T、CD4~+T and CD8~+T ceils determination results demonstrated that CD8~+T cells in pVAX1-hsp65 andpVAX1- hsp65-10 group were more than the control group with non-significant difference (P＞0.05 ).This also shows a MHCⅠtype cell immune response in experimental group.The amount.of CD4~+Tand CD3~+T cells in pVAX1-hsp65 group is significantly higher than the other groups.The IFN-γlevelin pVAX1- hsp65 and pVAX1- hsp65-10 group were higher than control group,but not yet reached astatistically significance (P＞0.05).However the result show that recombinant plasmids immunizationstrengthened the cell immunity of mice,and bivalent gene group is higher than single gene group.
Cavia cobaya was vaccinated with pVAX1- hsp65 and pVAX1- hsp65-10 recombinant plasmid,moreover,pVAX 1 and supersonic antigen of MAP as control.The allergy quarantine with avian bacillustuberculosis PPD indicated that there is significantly difference between the pVAXl-hsp65,pVAX1-hsp65-10 groups and supersonic antigen of MAP group (P＜0.01).This indicates that the Hsp65 andHsp 10 does not interfere with detection of Paratuberculosis allergy.
引文
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