分支杆菌新型表达系统的建立及其在基因重组卡介苗研究中的应用
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摘要
结核病是备受世界关注的一种主要公众传染性疾病。目前,全世界约有1/3人口(18.6亿)携带有结核分支杆菌(Mycobacterium tuberculosis,M.tb),每年约有800万新增病例,200万人死于结核病。而且,结核病的控制也因为多重耐药性(multidrug-resistant,MDR)菌株和艾滋病的出现使得本就十分严重的结核病疫情变得更加复杂化。目前,预防结核病唯一有效的疫苗是卡介苗(bacillusCalmette-Guerin,BCG),一种活的减毒牛型分支杆菌(M.bovis)。尽管BCG仍在许多国家广泛用于儿童的免疫接种,但其对于成人肺结核的的保护效率仍一直存在很大的争议。临床试验结果显示,卡介苗对肺结核的免疫保护力介于0～80%之间,差异性极大。因此,研究一种保护效力超过BCG的结核病新疫苗势在必行。
由于良好的免疫刺激效果以及广泛使用的安全性能,使得BCG可作为预防结核病以及其他传染病的优良细菌表达载体。利用大肠杆菌-分支杆菌穿梭载体,不同病原体来源的保护性候选抗原均可在BCG中克隆并表达,从而构建了相应更为高效的重组BCG(rBCG)疫苗。然而,由于BCG生长缓慢、构建的重组质粒表达水平偏低等因素的影响,其应用受到了一定的限制。近年来,随着分子生物学和基因工程技术的发展,构建可表达外源免疫优势抗原的rBCG研究发展迅速,并展现出了良好的应用前景。本文旨在建立一套分支杆菌的高效表达系统,以期实现目的基因在分支杆菌中的高水平表达;同时将其应用于rBCG的研究中,构建并筛选过表达结核杆菌嵌合抗原的基因重组卡介苗,并在动物水平上分析小鼠所诱导产生的抗原特异性细胞和体液免疫应答效果以评估其免疫原性。
以耻垢分支杆菌(M.smegmatis)乙酰胺酶编码基因启动子(pACE)为基础成功构建了分支杆菌可控表达载体pMF系列,在蛋白水平验证了pACE启动子的调控严谨性,并成功的实现了M.tb嵌合抗原在M.smegmatis中的高水平表达;进一步分析其表达形式,发现主要为可溶性蛋白,从而免除了E.coli异源表达系统中所常见的蛋白变性与复性问题的困扰;另外,6×His Tag标签的引入可方便的利用Ni~(2+)-NTA亲和层析实现重组抗原的一步纯化;尝试将重组诱导表达载体转化BCG,尽管加入诱导物,却并未实现嵌合抗原在rBCG中的高水平表达,提示以pACE为基础构建的表达质粒不适合作为rBCG的表达载体。
以E.coli lacZ为报告基因,在穿梭表达载体pMV261基础上进行改造,构建了分支杆菌启动子探针载体pMC210;将结核杆菌铁摄入蛋白上游调控序列/启动子区域(pfurA)进行定点突变,并将pfurA及其突变体以基因融合的方式克隆于lacZ基因上游,通过β-半乳糖苷酶活性测定分析其启动子强度。结果显示,在两种分支杆菌中(M.smegmatis和BCG),pfurA起始密码子GTG→ATG突变(pfurAa)仅能引起大约2倍β-半乳糖苷酶活性的升高,AT富集区序列6-bp的替换突变(pfurAm)可使转录活性升高4～6倍;如果是上述两者的联合突变(pfurAma),β-半乳糖苷酶活性则升高约10倍,比在分支杆菌中过表达蛋白时常用的强启动子phsp60也要高1.7～2倍。而且,有趣的是,pfurAs在慢速生长的BCG中比在快速生长的M.smegmatis中表现出了更高的β-半乳糖苷酶活性。
将带有不同pfurA-lacZ融合片段的rBCG::lacZ菌株感染鼠巨噬细胞RAW264.7单细胞层,发现所有rBCG::lacZ菌株在感染初期,β-半乳糖苷酶表达均迅速上调,1d后达到峰值;并可在细胞内持续表达,7 d后酶活性仍可维持在较之体外略高的水平。随后的动物实验结果显示,接种了rBCG::lacZ的小鼠成功的诱导出了增强的Th1型免疫应答反应,主要表现为高滴度IgG2a的产生以及高水平IFN-γ的分泌,且其所诱导产生分泌IFN-γ的T淋巴细胞数量和rBCG::lacZ所表达的β-gal抗原水平呈正相关性。提示pfurAs启动子系列非常适合在rBCG中驱动异源基因的表达,且以其为基础构建的重组卡介苗可诱导机体产生抗原特异性Th1为主的免疫应答反应。
因而,pfurA及其突变体被用来构建分支杆菌的差异表达载体pMFA系列。应用pMFA载体系列,成功的实现了M.tb嵌合抗原在M.smegmatis及BCG中以不同水平的差异性表达;具有起始密码子及AT富集区联合突变的pfurAma导致了最高水平的基因表达,这与β-半乳糖苷酶活性测定结果相一致。接着,以带有不同pfurA-ag856a2融合片段的rBCG856A2免疫小鼠,进一步在动物水平验证了该rBCG856A2可以在小鼠体内分别诱导产生Ag85A、ESAT-6抗原特异的细胞免疫应答和体液免疫应答,说明嵌合基因rBCG856A2具有良好的免疫原性。另外,为了配合嵌合基因rBCG856A2的免疫检测工作,我们还分别在E.coli中表达与纯化了重组蛋白Ag85A、ESAT-6以及嵌合抗原Ag856A2,并同时制备了Anti-Ag85A及Anti-ESAT-6的小鼠单克隆抗体。接下来我们的工作重点将是进行小鼠攻击试验,以评估嵌合基因重组卡介苗的免疫保护效果,为日后的临床试验打下基础。
Tuberculosis(TB),though curable,still remains a major public health challenge worldwide.Mycobacterium tuberculosis(M.tb),the primary etiologic agent of TB, caused approximately 8 million new cases and 2 million deaths every year around the world.It has been estimated that 250,000 deaths occurred annually in China,among 6 million active TB patients at present.Furthermore,control of TB has been further complicated by the emergence of multidrug-resistant(MDR) M.tb strains and the human immunodeficiency virus(HIV) epidemic.The current vaccine,Mycobacterium bovis bacille Calmette-Guérin(BCG),a live attenuated vaccine derived from the bovine tuberculosis bacillus in the early 1900s,is still being administered to children in many countries,but its efficacy in protecting against TB,especially against the adult form of TB,remains controversial.BCG clinical trials showed its efficacy is highly variable,ranging from 0%to 80%.Thus,a new vaccine against TB more potent than BCG is urgently needed.
Despite these unsatisfactory problems of BCG vaccine,its excellent immunostimulatory properties and proven safety for human use have led to the concept of recombinant BCG(rBCG)-based vaccines against TB and other infections. It has been reported that various protective candidate antigens could be cloned and expressed in BCG to make it more potent vaccine,by utilizing the E.colimycobacteria shuttle expression vectors.However,its application is restricted by slow-growing of BCG and low-level expression of recombinant plasmids.In the near past years,with the development of molecular biology and genetic engineering,there are many important progresses on rBCG expressing heterlogous immunodominant antigen,which shows a good prospect for its application.This study mainly focuses on establishing the mycobacterial high-level expression systems and to achieve the over-expression of target gene in mycobacteria.Based on the novel expression systems,the recombinant BCG vaccine strains with high-level expression of M.tb chimeric antigen,which showed excellent immunogenicity in our previous studies, were tried to construct,and were evaluated their immunogenicities in the animal experiments by analysis of the antigen-specific cellular and humoral immune response induced on the BALB/c mice.
Using the regulatory region of M.smegmatis acetamidase(pACE) as promoter, the mycobacterial inducible expression vectors,pMF series,were constructed successfully.The acetamidase promoter was confirmed to be regulated tightly on the protein level,and the M.tb chimeric antigen was achieved to high-level expression in M.smegmatis by virture of the pMF series as expression vectors.The recombinant proteins obtained from M.smegmatis were mostly solube,which will be superiority over the same protein purified from E.coli expression systems.Furthermore,the addition of 6×His tag to the C-terminus of the recombinant protein facilitates the simple and effecitive purification of our model protein by Ni2~+-NTA affinity chromatography.However,the M.tb chimeric antigen was not expressed at high levels under the control of pACE in rBCG strains in spite of the addition of inducer acetamide;this suggests that the expression vectors based on the M.smegmatis acetamidase promoter seem not to be suited to drive expression of target antigen in BCG host.
A simple and efficient promoter trapping vector,pMC210,was constructed with the promoterless E.coli lacZ gene as the reporter,modified on the E.colimycobacteiral shuttle plasmid pMV261.The M.tb furA gene promoter(pfurA) and its mutants were obtained by direct mutagenesis of the furA operator sequence,and these resulting mutated and the prototype pfurAs were then gene-fused to the immediately upstream of the lacZ reporter to analyze their in vivo transcrioption activities in M. smegmatis or M.bovis BCG.Theβ-galactosidase assay results showed that in both hosts,change of the initial codon GTG to ATG(pfurAα) only caused about twice increase of the transcription activity,while the 6-bp substitution in the 23-bp AT-rich region(pfurAm),which is conserved in the mycobacteria and is essential for FurA binding,caused about 4～6 times increase of the activity.With the combination of both mutations(pfurAma),theβ-galactosidase activity increased about 10 times,which was 1.7～2 times higher than the BCG phsp60,the strong promoter used widely for over-expressing proteins in mycobacteria.It is interesting to notice that the pfurA series exhibited higherβ-galactosidase activity in the slow-growing M.bovis BCG than in the fast-growing M.smegmatis.
Subsequently,rBCG::lacZ strains transformed with the different pfurAs-lacZ construct were infected the murine macrophage RAW264.7 monolayer,the results showed thatβ-galactosidase activities were upregulated immediately in all of the rBCG::lacZ strains at the early infection,and were then persisted at levels higher than those recorded for rBCG::lacZ before macrophage infection,up to 7 days after infection.The next results on the animal experiment showed that all of mice immunized with the different rBCG::lacZ vaccines except pfurA-lacZ construct,were induced an enhanced Th1 immune response,characterized by increased production of antibodies of IgG2a subtype and higher secretion of IFN-γ.In addition,the amounts of T lymphocytes secreting IFN-γwere associated with theβ-gal levels expressed in the rBCG::lacZ strains.These suggests that pfurA series were seem to be suitable especially to drive gene expression in mycobacteria and rBCG vaccines based on pfurA series would induce production of antigen-specific Th1 immune response.
Therefore,the prototype and the mutated pfurAs were used to construct mycobacterial differential expression vectors pMFA series.Employing the pMFA vectors,the M.tb chimericαg856α2 gene was expressed at various levels under the control of the different pfurAs in the recombinant M.smegrnatis and rBCG strains,and the double mutation on both 6-bp substitution in the FurA binding AT-rich region and GTG initiation codon to ATG variation,pfurAma,caused the highest level of gene expression level,which is consistent with the result ofβ-galactosidase assay. Subsequently,the BALB/c mice were immunized with the chimeric gene recombinant BCG(rBCG856A2) vaccines transformed with the different pfurA-αg856α2 constructs,and the results confirmed the good immunogenicities of rBCG856A2 vaccines,based on the anti-Ag85A and anti-ESAT-6 specific cellular and humoral immune responses.In order to facilitate the immune detection of rBCG856A2 vaccines,recombinant chimeric antigen Ag856A2(rAg856A2),rAg85A,and rESAT-6 were expressed and purified from E.eoli,respectively;and the murine anti-Ag85A and anti-ESAT-6 monoantibodies(mAbs) were also prepared.Next,we will focus on the challegene experiment on animal models in order to evaluate the immune protective efficacy,which would pave the way for the later clinical experiment of rBCG856A2 vaccines.
由于良好的免疫刺激效果以及广泛使用的安全性能,使得BCG可作为预防结核病以及其他传染病的优良细菌表达载体。利用大肠杆菌-分支杆菌穿梭载体,不同病原体来源的保护性候选抗原均可在BCG中克隆并表达,从而构建了相应更为高效的重组BCG(rBCG)疫苗。然而,由于BCG生长缓慢、构建的重组质粒表达水平偏低等因素的影响,其应用受到了一定的限制。近年来,随着分子生物学和基因工程技术的发展,构建可表达外源免疫优势抗原的rBCG研究发展迅速,并展现出了良好的应用前景。本文旨在建立一套分支杆菌的高效表达系统,以期实现目的基因在分支杆菌中的高水平表达;同时将其应用于rBCG的研究中,构建并筛选过表达结核杆菌嵌合抗原的基因重组卡介苗,并在动物水平上分析小鼠所诱导产生的抗原特异性细胞和体液免疫应答效果以评估其免疫原性。
以耻垢分支杆菌(M.smegmatis)乙酰胺酶编码基因启动子(pACE)为基础成功构建了分支杆菌可控表达载体pMF系列,在蛋白水平验证了pACE启动子的调控严谨性,并成功的实现了M.tb嵌合抗原在M.smegmatis中的高水平表达;进一步分析其表达形式,发现主要为可溶性蛋白,从而免除了E.coli异源表达系统中所常见的蛋白变性与复性问题的困扰;另外,6×His Tag标签的引入可方便的利用Ni~(2+)-NTA亲和层析实现重组抗原的一步纯化;尝试将重组诱导表达载体转化BCG,尽管加入诱导物,却并未实现嵌合抗原在rBCG中的高水平表达,提示以pACE为基础构建的表达质粒不适合作为rBCG的表达载体。
以E.coli lacZ为报告基因,在穿梭表达载体pMV261基础上进行改造,构建了分支杆菌启动子探针载体pMC210;将结核杆菌铁摄入蛋白上游调控序列/启动子区域(pfurA)进行定点突变,并将pfurA及其突变体以基因融合的方式克隆于lacZ基因上游,通过β-半乳糖苷酶活性测定分析其启动子强度。结果显示,在两种分支杆菌中(M.smegmatis和BCG),pfurA起始密码子GTG→ATG突变(pfurAa)仅能引起大约2倍β-半乳糖苷酶活性的升高,AT富集区序列6-bp的替换突变(pfurAm)可使转录活性升高4～6倍;如果是上述两者的联合突变(pfurAma),β-半乳糖苷酶活性则升高约10倍,比在分支杆菌中过表达蛋白时常用的强启动子phsp60也要高1.7～2倍。而且,有趣的是,pfurAs在慢速生长的BCG中比在快速生长的M.smegmatis中表现出了更高的β-半乳糖苷酶活性。
将带有不同pfurA-lacZ融合片段的rBCG::lacZ菌株感染鼠巨噬细胞RAW264.7单细胞层,发现所有rBCG::lacZ菌株在感染初期,β-半乳糖苷酶表达均迅速上调,1d后达到峰值;并可在细胞内持续表达,7 d后酶活性仍可维持在较之体外略高的水平。随后的动物实验结果显示,接种了rBCG::lacZ的小鼠成功的诱导出了增强的Th1型免疫应答反应,主要表现为高滴度IgG2a的产生以及高水平IFN-γ的分泌,且其所诱导产生分泌IFN-γ的T淋巴细胞数量和rBCG::lacZ所表达的β-gal抗原水平呈正相关性。提示pfurAs启动子系列非常适合在rBCG中驱动异源基因的表达,且以其为基础构建的重组卡介苗可诱导机体产生抗原特异性Th1为主的免疫应答反应。
因而,pfurA及其突变体被用来构建分支杆菌的差异表达载体pMFA系列。应用pMFA载体系列,成功的实现了M.tb嵌合抗原在M.smegmatis及BCG中以不同水平的差异性表达;具有起始密码子及AT富集区联合突变的pfurAma导致了最高水平的基因表达,这与β-半乳糖苷酶活性测定结果相一致。接着,以带有不同pfurA-ag856a2融合片段的rBCG856A2免疫小鼠,进一步在动物水平验证了该rBCG856A2可以在小鼠体内分别诱导产生Ag85A、ESAT-6抗原特异的细胞免疫应答和体液免疫应答,说明嵌合基因rBCG856A2具有良好的免疫原性。另外,为了配合嵌合基因rBCG856A2的免疫检测工作,我们还分别在E.coli中表达与纯化了重组蛋白Ag85A、ESAT-6以及嵌合抗原Ag856A2,并同时制备了Anti-Ag85A及Anti-ESAT-6的小鼠单克隆抗体。接下来我们的工作重点将是进行小鼠攻击试验,以评估嵌合基因重组卡介苗的免疫保护效果,为日后的临床试验打下基础。
Tuberculosis(TB),though curable,still remains a major public health challenge worldwide.Mycobacterium tuberculosis(M.tb),the primary etiologic agent of TB, caused approximately 8 million new cases and 2 million deaths every year around the world.It has been estimated that 250,000 deaths occurred annually in China,among 6 million active TB patients at present.Furthermore,control of TB has been further complicated by the emergence of multidrug-resistant(MDR) M.tb strains and the human immunodeficiency virus(HIV) epidemic.The current vaccine,Mycobacterium bovis bacille Calmette-Guérin(BCG),a live attenuated vaccine derived from the bovine tuberculosis bacillus in the early 1900s,is still being administered to children in many countries,but its efficacy in protecting against TB,especially against the adult form of TB,remains controversial.BCG clinical trials showed its efficacy is highly variable,ranging from 0%to 80%.Thus,a new vaccine against TB more potent than BCG is urgently needed.
Despite these unsatisfactory problems of BCG vaccine,its excellent immunostimulatory properties and proven safety for human use have led to the concept of recombinant BCG(rBCG)-based vaccines against TB and other infections. It has been reported that various protective candidate antigens could be cloned and expressed in BCG to make it more potent vaccine,by utilizing the E.colimycobacteria shuttle expression vectors.However,its application is restricted by slow-growing of BCG and low-level expression of recombinant plasmids.In the near past years,with the development of molecular biology and genetic engineering,there are many important progresses on rBCG expressing heterlogous immunodominant antigen,which shows a good prospect for its application.This study mainly focuses on establishing the mycobacterial high-level expression systems and to achieve the over-expression of target gene in mycobacteria.Based on the novel expression systems,the recombinant BCG vaccine strains with high-level expression of M.tb chimeric antigen,which showed excellent immunogenicity in our previous studies, were tried to construct,and were evaluated their immunogenicities in the animal experiments by analysis of the antigen-specific cellular and humoral immune response induced on the BALB/c mice.
Using the regulatory region of M.smegmatis acetamidase(pACE) as promoter, the mycobacterial inducible expression vectors,pMF series,were constructed successfully.The acetamidase promoter was confirmed to be regulated tightly on the protein level,and the M.tb chimeric antigen was achieved to high-level expression in M.smegmatis by virture of the pMF series as expression vectors.The recombinant proteins obtained from M.smegmatis were mostly solube,which will be superiority over the same protein purified from E.coli expression systems.Furthermore,the addition of 6×His tag to the C-terminus of the recombinant protein facilitates the simple and effecitive purification of our model protein by Ni2~+-NTA affinity chromatography.However,the M.tb chimeric antigen was not expressed at high levels under the control of pACE in rBCG strains in spite of the addition of inducer acetamide;this suggests that the expression vectors based on the M.smegmatis acetamidase promoter seem not to be suited to drive expression of target antigen in BCG host.
A simple and efficient promoter trapping vector,pMC210,was constructed with the promoterless E.coli lacZ gene as the reporter,modified on the E.colimycobacteiral shuttle plasmid pMV261.The M.tb furA gene promoter(pfurA) and its mutants were obtained by direct mutagenesis of the furA operator sequence,and these resulting mutated and the prototype pfurAs were then gene-fused to the immediately upstream of the lacZ reporter to analyze their in vivo transcrioption activities in M. smegmatis or M.bovis BCG.Theβ-galactosidase assay results showed that in both hosts,change of the initial codon GTG to ATG(pfurAα) only caused about twice increase of the transcription activity,while the 6-bp substitution in the 23-bp AT-rich region(pfurAm),which is conserved in the mycobacteria and is essential for FurA binding,caused about 4～6 times increase of the activity.With the combination of both mutations(pfurAma),theβ-galactosidase activity increased about 10 times,which was 1.7～2 times higher than the BCG phsp60,the strong promoter used widely for over-expressing proteins in mycobacteria.It is interesting to notice that the pfurA series exhibited higherβ-galactosidase activity in the slow-growing M.bovis BCG than in the fast-growing M.smegmatis.
Subsequently,rBCG::lacZ strains transformed with the different pfurAs-lacZ construct were infected the murine macrophage RAW264.7 monolayer,the results showed thatβ-galactosidase activities were upregulated immediately in all of the rBCG::lacZ strains at the early infection,and were then persisted at levels higher than those recorded for rBCG::lacZ before macrophage infection,up to 7 days after infection.The next results on the animal experiment showed that all of mice immunized with the different rBCG::lacZ vaccines except pfurA-lacZ construct,were induced an enhanced Th1 immune response,characterized by increased production of antibodies of IgG2a subtype and higher secretion of IFN-γ.In addition,the amounts of T lymphocytes secreting IFN-γwere associated with theβ-gal levels expressed in the rBCG::lacZ strains.These suggests that pfurA series were seem to be suitable especially to drive gene expression in mycobacteria and rBCG vaccines based on pfurA series would induce production of antigen-specific Th1 immune response.
Therefore,the prototype and the mutated pfurAs were used to construct mycobacterial differential expression vectors pMFA series.Employing the pMFA vectors,the M.tb chimericαg856α2 gene was expressed at various levels under the control of the different pfurAs in the recombinant M.smegrnatis and rBCG strains,and the double mutation on both 6-bp substitution in the FurA binding AT-rich region and GTG initiation codon to ATG variation,pfurAma,caused the highest level of gene expression level,which is consistent with the result ofβ-galactosidase assay. Subsequently,the BALB/c mice were immunized with the chimeric gene recombinant BCG(rBCG856A2) vaccines transformed with the different pfurA-αg856α2 constructs,and the results confirmed the good immunogenicities of rBCG856A2 vaccines,based on the anti-Ag85A and anti-ESAT-6 specific cellular and humoral immune responses.In order to facilitate the immune detection of rBCG856A2 vaccines,recombinant chimeric antigen Ag856A2(rAg856A2),rAg85A,and rESAT-6 were expressed and purified from E.eoli,respectively;and the murine anti-Ag85A and anti-ESAT-6 monoantibodies(mAbs) were also prepared.Next,we will focus on the challegene experiment on animal models in order to evaluate the immune protective efficacy,which would pave the way for the later clinical experiment of rBCG856A2 vaccines.
引文
[1]Frieden TR,Sterling TR,Munsiff SS,Watt CJ,Dye C.Tuberculosis[J].Lance!2003;362(9387):887-99.
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