抗日本血吸虫感染表位PDDV疫苗的研究
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摘要
血吸虫病(schis tosomiasis)是全球第二大严重危害人类健康的寄生虫病，我国有现症患者80余万，受威胁人口达1亿。虽然经过半个多世纪的控制努力，血吸虫病的人群感染和流行已大大降低，但是作为一种严重的人兽共患病，仍有许多问题尚未解决。
控制血吸虫病的传播和流行需采取以吡喹酮反复群体化疗，辅以灭螺等的综合防治手段。但随着血吸虫的感染和反复再感染，以及吡喹酮耐药性的出现，血吸虫病疫苗的发展提到日程上来。有效的抗血吸虫疫苗不仅能长期控制血吸虫病，甚至可能消灭它。而阐明血吸虫病免疫保护的机制是研制血吸虫病疫苗的前提条件。目前，有关抗血吸虫保护力的相关免疫学机制仍不明确。
本研究拟从诱导宿主保护性免疫应答为出发点，用生物信息学工具从不同疫苗候选分子中筛选T／B细胞表位，以粒细胞一巨噬细胞集落刺激因子(GM-CSF)为佐剂，利用阳离子肽技术制备表位肽-核酸双疫苗(PDDV)，并观察单个及混合表位PDDV在小鼠体内诱导的免疫应答，及其对小鼠抗日本血吸虫感染、抗病理的作用，为探索日本血吸虫病疫苗研制的新途径和探讨日本血吸虫感染的保护性免疫机制提供有益的实验研究资料。为此，本文进行了以下几个方面的研究。
一、生物信息学分析、预测日本血吸虫抗原分子表位
为了优化疫苗的设计，分析预测日本血吸虫病疫苗候选抗原分子中的T／B细胞表位，应用多种在线数据库和软件分析10个日本血吸虫潜在疫苗候选抗原分子(Sj14，Sj97，sj14-3-3，sj22.6，sj23，sj26，Sj28，sj338，sj62，sjTPI)，预测人类基因型HLA-DRB1*0401、HLA-A*0201以及C57BL／6小鼠基因型H-2b(H-2Kb、H-2Db)的对应细胞表位，包括MHCⅠ类分子相关的CTL表位、MHCⅡ类分子相关的Th表位和抗体相关的B细胞表位。并进行蛋白酶体水解位点预测，以剔除表位递呈至体内可能被水解的片段。再用BLAST比对与研究对象(人／小鼠)相应蛋白分子的同源性，剔除同源性高的表位以避免自身免疫反应。最终根据10个抗原分子的T／B细胞表位的表位分析结果，表位蛋白酶体水解位点预测以及同源性比对的结果，综合后得到小鼠基因型的日本血吸虫抗原分子CTL、Th和B细胞表位各3个，用于后续研究。
二、抗日本血吸虫感染表位PDDV疫苗的构建
为了更好的提高抗日本血吸虫感染疫苗的效果，采取了PDDV的形式。根据研究一中预测所得的9个表位序列，在每个表位的N端加上18个赖氨酸的阳离子肽作为连接桥，合成相应的肽段，并合成带有酶切位点的互补的表位相应DNA正负链。将互补DNA正负链退火后的片段插入双酶切过的载体PUMVC1-mGM-CSF，构建含抗原表位肽编码基因的重组真核表达载体，并通过双酶切实验和DNA测序鉴定。测序结果显示构建的载体中含有相应表位肽编码基因序列。同时构建不同组合的CTL、Th和B表位肽编码基因串联的表达载体。再将含抗原表位肽DNA的质粒与相应肽段通过正负电荷作用连接成纳米大小的颗粒，构建成Peptide-DNA Dual Vaccine(PDDV)。并对不同制备条件下的PDDV通过电泳阻滞试验、DNaseⅠ保护性试验和电镜观察对其理化特性进行鉴定，选取最优化的条件(NaC1的浓度为150mmol／L，肽与质粒DNA比值为4)制备表位PDDV。在这个优化的条件下制备出的PDDV可以保护DNA不被核酸酶降解，电镜下观察颗粒大小均匀，直径约15nm左右，符合抗原递呈的要求。最终制备的含有不同表位的PDDV，用于小鼠模型的进一步研究。
三、表位PDDV在小鼠模型上的免疫学特性及免疫保护性的实验研究
为研究表位PDDV在小鼠模型上的免疫学特性，以及在抗日本血吸虫感染和抗病理方面的作用。将小鼠分为29组，制备好的单表位PDDV或CTL、Th、B混合表位PDDV按照每只小鼠每次100μl进行免疫，注射PBS作为对照，每2周免疫一次，共3次，末次免疫后1周剖杀6只小鼠／组，取淋巴结和脾脏细胞进行~(51)Cr释放试验检测细胞杀伤力、~3H掺入法检测细胞增殖以及ELISA检测细胞因子IFN-γ和IL-4的检测；取血清进行ELISA检测抗体IgG及其亚类IgGl和IgG2a水平。在CTL表位PDDV小鼠组可见显著的细胞杀伤效应；在Th表位PDDV组可见增高的细胞因子及细胞增殖反应；而B表位PDDV组产生了高水平抗体的免疫应答。其中Th表位T3和B细胞表位B3制备的PDDV的免疫应答尤为显著。这表明PDDV可以在体内诱导出抗原特异性的细胞免疫应答和抗体免疫应答。不同类型的表位PDDV混合后免疫小鼠的各种免疫反应并不如单表位PDDV显著。末次免疫2周后用40条尾蚴攻击感染，感染6周后剖杀小鼠，回收小鼠体内成虫进行计数；消化肝脏在显微镜下计数肝内虫卵数目，并将肝脏组织制成病理切片，观察肝脏虫卵肉芽肿的数目和大小。根据减虫率、减卵率，以及病理切片观察结果，CTL表位组PDDV未显示出有效保护力，T3表位与B3表位PDDV可诱导小鼠产生部分免疫保护力。这表明Th／B表位PDDV具有抗日本血吸虫感染和病理损害的作用。
综上，本研究中利用生物信息学工具从不同疫苗候选分子中筛选了T／B细胞表位，以GM-CSF为佐剂，构建了含预测表位编码基因的真核表达载体。将载体与合成表位肽利用阳离子肽技术在最优化的条件下制备表位肽一核酸双疫苗(PDDV)，并观察了单个及混合表位PDDV在小鼠体内诱导的免疫应答，及其对小鼠抗日本血吸虫感染、抗病理的作用。其中单个T3和B3表位PDDV免疫小鼠产生较高的抗血吸虫感染的免疫保护力。这表明，血吸虫抗原分子的表位PDDV具有一定的抗血吸虫感染的作用，而如何提高混合或者复合表位PDDV的免疫保护效果尚有待进一步研究。
Schistosomiasis, the second major parasitic disease in the worldafter malaria, affects mainly developing countries. There are 200 mil-lion people worldwide infected with schistosomes, resulting in morethan 250,000 deaths annually. Although the last half-century of schisto-somiasis control programs have brought down the overall prevalence ofhuman infection with Schistosoma japonicum, the parasitic disease re-mains a serious zoonosis with many problems unsolved, especially re-infection and reemergence of prevalence. An efficacious vaccine againstSchistosomiasis japonica would represent a significant addition to thecurrent arsenal of control tools, particularly in the framework of an in-tegrated control approach. However, the fact remains that after manyyears of trying, a rationally designed effective anti-schistosome vaccinehas yet to be developed. As a prophylactic measure, using vaccinewould be the ideal method for sustainable control of schistosomiasis,alone or in combination with anthelmintic drugs and the development ofan efficient vaccine is required to make the elimination of schistosomi-asis achievable
In the past years, many laboratories have attempted to identifythe schistosome antigens that induce the partially protective immuneresponse. Vaccinations with synthetic or recombinant antigens havesuccessfully induced partial protection and/or reduced female fecundityin animal models. However, epitope-based vaccine offers the prospectof targeted immunity resulting in safer and more effective anti-gen-specific immune responses. The host's immunity against schisto-some infection is mainly cellular and humoral immune response, whichis mediated by the specific T cells and B cells. Consequently, identifica-tion of these T/B-cell epitopes as safe effective immunogens representsa pivotal step for the study of pathogenesis and immunity and especiallyfor the development of vaccine against schistosomiasis
To optimize the vaccine design, we undertook studies to identifyT/B epitope on ten protective antigens by bioinformatics in order toidentify the potential protective epitopes, including Sj14, Sj97, Sj14-3-3,Sj22.6, Sj23, Sj26, Sj28, Sj338, Sj62 and SjTPI. Several online T/B cell-related databases and analysis tools were chosen according to the hu-man allele HLA-DRB1*0401, HLA-A*0201 or C57BL/6 mouse H-2b(H-2Kb、H-2Db). And the proteasomal cleavage sites were predictedand excluded to protect the epitope from being digested. The epitopespredicted above were screened on BLAST to exclude the homologousones. Eventually, three epitopes of CTL, Th and B cell, respectively were chosen for further study.
To improve the efficacy of the vaccine, peptide-DNA dual vac-cine (PDDV) strategy was used, which was a nanometer-size particleantigen delivery system constructed by combination of the epitope fromthe protective antigen and the plasmid encoding the same epitope. Theepitopes containing 18 lysines which acted as the bridge of the peptideand its control peptide of 18 lysines (18K) were synthesized and puri-fied. The oligonucleotides encoding the epitopes with restrictive en-zyme (RE) Sal I site at 5' terminus and EcoR I site at 3' terminus werealso synthesized and insert into expression plasmidpUMVC1-mGM-CSF. The procedure for preparing PDDV was per-formed by titrating peptide into a solution of the corresponding plasmid.The input molar ratio of peptide to DNA (r) was the ratio of moles oflysine to nucleotide (NH4~+/PO3~-). PDDVs prepared was identified byDNA retardation assay, DNase I digestion assay and electron micros-copy to choose the best condition of preparation. The optimized PDDVswere prepared for the animal experiments.
C57BL/6 mice were divided into 29 groups, 14 mice each group.Each mouse was injected subcutaneously (s.c) in the back with 100μl ofsolution containing 28μg of peptide and 10μg of plasmid pGT or pGrespectively, or PBS (control group). The immunization was repeatedwith 14-day interval. One week after the final vaccination, 6 mice from each group were sacrificed for the detection of the cellular and humoralimmune response. CTL activity of the CD8+ effector cells was assessedin a standard 4-h ~(51)Cr-release assay. T cell proliferation and cytokineswere detected for evaluation of Th cellular immune response. And anti-bodies were measured for evaluation of humoral immune response. Theresults showed that CTL responses, Th response and antibodies wereinduced by the CTL, Th and B-cell epitope-PDDV respectively. But therelevant immune response was not detected in the groups immunizedwith mixed epitope PDDVs.
Two weeks after the last vaccination, 8 mice of each group werechallenged percutaneously with 40 cercariae of S. j aponicum. Six weeksafter challenge, all vaccinated and control mice were sacrificed andperfusion was undertaken with saline containing heparin to recover theadult worms. The livers were digested and the number of eggs was de-termined by microscopic examination. The worm/egg reduction ratewas calculated. After portal perfusion, mice livers were dissected andstained with hematoxylin and eosin (HE) for microscopic examination.The number of egg granulomas was counted and the sizes of noncon-fluent granulomas formed around a single egg containing a maturemiracidium were assessed using a video micrometer. The resultsshowed that several PDDVs induced promising protection. Especially,T3 epitope PDDV induced both cellular and humoral immune responses, achieved 33.8%～44.7% protections against S. japonicum infection anddiminished egg granulomas in the livers of challenged mice.
控制血吸虫病的传播和流行需采取以吡喹酮反复群体化疗，辅以灭螺等的综合防治手段。但随着血吸虫的感染和反复再感染，以及吡喹酮耐药性的出现，血吸虫病疫苗的发展提到日程上来。有效的抗血吸虫疫苗不仅能长期控制血吸虫病，甚至可能消灭它。而阐明血吸虫病免疫保护的机制是研制血吸虫病疫苗的前提条件。目前，有关抗血吸虫保护力的相关免疫学机制仍不明确。
本研究拟从诱导宿主保护性免疫应答为出发点，用生物信息学工具从不同疫苗候选分子中筛选T／B细胞表位，以粒细胞一巨噬细胞集落刺激因子(GM-CSF)为佐剂，利用阳离子肽技术制备表位肽-核酸双疫苗(PDDV)，并观察单个及混合表位PDDV在小鼠体内诱导的免疫应答，及其对小鼠抗日本血吸虫感染、抗病理的作用，为探索日本血吸虫病疫苗研制的新途径和探讨日本血吸虫感染的保护性免疫机制提供有益的实验研究资料。为此，本文进行了以下几个方面的研究。
一、生物信息学分析、预测日本血吸虫抗原分子表位
为了优化疫苗的设计，分析预测日本血吸虫病疫苗候选抗原分子中的T／B细胞表位，应用多种在线数据库和软件分析10个日本血吸虫潜在疫苗候选抗原分子(Sj14，Sj97，sj14-3-3，sj22.6，sj23，sj26，Sj28，sj338，sj62，sjTPI)，预测人类基因型HLA-DRB1*0401、HLA-A*0201以及C57BL／6小鼠基因型H-2b(H-2Kb、H-2Db)的对应细胞表位，包括MHCⅠ类分子相关的CTL表位、MHCⅡ类分子相关的Th表位和抗体相关的B细胞表位。并进行蛋白酶体水解位点预测，以剔除表位递呈至体内可能被水解的片段。再用BLAST比对与研究对象(人／小鼠)相应蛋白分子的同源性，剔除同源性高的表位以避免自身免疫反应。最终根据10个抗原分子的T／B细胞表位的表位分析结果，表位蛋白酶体水解位点预测以及同源性比对的结果，综合后得到小鼠基因型的日本血吸虫抗原分子CTL、Th和B细胞表位各3个，用于后续研究。
二、抗日本血吸虫感染表位PDDV疫苗的构建
为了更好的提高抗日本血吸虫感染疫苗的效果，采取了PDDV的形式。根据研究一中预测所得的9个表位序列，在每个表位的N端加上18个赖氨酸的阳离子肽作为连接桥，合成相应的肽段，并合成带有酶切位点的互补的表位相应DNA正负链。将互补DNA正负链退火后的片段插入双酶切过的载体PUMVC1-mGM-CSF，构建含抗原表位肽编码基因的重组真核表达载体，并通过双酶切实验和DNA测序鉴定。测序结果显示构建的载体中含有相应表位肽编码基因序列。同时构建不同组合的CTL、Th和B表位肽编码基因串联的表达载体。再将含抗原表位肽DNA的质粒与相应肽段通过正负电荷作用连接成纳米大小的颗粒，构建成Peptide-DNA Dual Vaccine(PDDV)。并对不同制备条件下的PDDV通过电泳阻滞试验、DNaseⅠ保护性试验和电镜观察对其理化特性进行鉴定，选取最优化的条件(NaC1的浓度为150mmol／L，肽与质粒DNA比值为4)制备表位PDDV。在这个优化的条件下制备出的PDDV可以保护DNA不被核酸酶降解，电镜下观察颗粒大小均匀，直径约15nm左右，符合抗原递呈的要求。最终制备的含有不同表位的PDDV，用于小鼠模型的进一步研究。
三、表位PDDV在小鼠模型上的免疫学特性及免疫保护性的实验研究
为研究表位PDDV在小鼠模型上的免疫学特性，以及在抗日本血吸虫感染和抗病理方面的作用。将小鼠分为29组，制备好的单表位PDDV或CTL、Th、B混合表位PDDV按照每只小鼠每次100μl进行免疫，注射PBS作为对照，每2周免疫一次，共3次，末次免疫后1周剖杀6只小鼠／组，取淋巴结和脾脏细胞进行~(51)Cr释放试验检测细胞杀伤力、~3H掺入法检测细胞增殖以及ELISA检测细胞因子IFN-γ和IL-4的检测；取血清进行ELISA检测抗体IgG及其亚类IgGl和IgG2a水平。在CTL表位PDDV小鼠组可见显著的细胞杀伤效应；在Th表位PDDV组可见增高的细胞因子及细胞增殖反应；而B表位PDDV组产生了高水平抗体的免疫应答。其中Th表位T3和B细胞表位B3制备的PDDV的免疫应答尤为显著。这表明PDDV可以在体内诱导出抗原特异性的细胞免疫应答和抗体免疫应答。不同类型的表位PDDV混合后免疫小鼠的各种免疫反应并不如单表位PDDV显著。末次免疫2周后用40条尾蚴攻击感染，感染6周后剖杀小鼠，回收小鼠体内成虫进行计数；消化肝脏在显微镜下计数肝内虫卵数目，并将肝脏组织制成病理切片，观察肝脏虫卵肉芽肿的数目和大小。根据减虫率、减卵率，以及病理切片观察结果，CTL表位组PDDV未显示出有效保护力，T3表位与B3表位PDDV可诱导小鼠产生部分免疫保护力。这表明Th／B表位PDDV具有抗日本血吸虫感染和病理损害的作用。
综上，本研究中利用生物信息学工具从不同疫苗候选分子中筛选了T／B细胞表位，以GM-CSF为佐剂，构建了含预测表位编码基因的真核表达载体。将载体与合成表位肽利用阳离子肽技术在最优化的条件下制备表位肽一核酸双疫苗(PDDV)，并观察了单个及混合表位PDDV在小鼠体内诱导的免疫应答，及其对小鼠抗日本血吸虫感染、抗病理的作用。其中单个T3和B3表位PDDV免疫小鼠产生较高的抗血吸虫感染的免疫保护力。这表明，血吸虫抗原分子的表位PDDV具有一定的抗血吸虫感染的作用，而如何提高混合或者复合表位PDDV的免疫保护效果尚有待进一步研究。
Schistosomiasis, the second major parasitic disease in the worldafter malaria, affects mainly developing countries. There are 200 mil-lion people worldwide infected with schistosomes, resulting in morethan 250,000 deaths annually. Although the last half-century of schisto-somiasis control programs have brought down the overall prevalence ofhuman infection with Schistosoma japonicum, the parasitic disease re-mains a serious zoonosis with many problems unsolved, especially re-infection and reemergence of prevalence. An efficacious vaccine againstSchistosomiasis japonica would represent a significant addition to thecurrent arsenal of control tools, particularly in the framework of an in-tegrated control approach. However, the fact remains that after manyyears of trying, a rationally designed effective anti-schistosome vaccinehas yet to be developed. As a prophylactic measure, using vaccinewould be the ideal method for sustainable control of schistosomiasis,alone or in combination with anthelmintic drugs and the development ofan efficient vaccine is required to make the elimination of schistosomi-asis achievable
In the past years, many laboratories have attempted to identifythe schistosome antigens that induce the partially protective immuneresponse. Vaccinations with synthetic or recombinant antigens havesuccessfully induced partial protection and/or reduced female fecundityin animal models. However, epitope-based vaccine offers the prospectof targeted immunity resulting in safer and more effective anti-gen-specific immune responses. The host's immunity against schisto-some infection is mainly cellular and humoral immune response, whichis mediated by the specific T cells and B cells. Consequently, identifica-tion of these T/B-cell epitopes as safe effective immunogens representsa pivotal step for the study of pathogenesis and immunity and especiallyfor the development of vaccine against schistosomiasis
To optimize the vaccine design, we undertook studies to identifyT/B epitope on ten protective antigens by bioinformatics in order toidentify the potential protective epitopes, including Sj14, Sj97, Sj14-3-3,Sj22.6, Sj23, Sj26, Sj28, Sj338, Sj62 and SjTPI. Several online T/B cell-related databases and analysis tools were chosen according to the hu-man allele HLA-DRB1*0401, HLA-A*0201 or C57BL/6 mouse H-2b(H-2Kb、H-2Db). And the proteasomal cleavage sites were predictedand excluded to protect the epitope from being digested. The epitopespredicted above were screened on BLAST to exclude the homologousones. Eventually, three epitopes of CTL, Th and B cell, respectively were chosen for further study.
To improve the efficacy of the vaccine, peptide-DNA dual vac-cine (PDDV) strategy was used, which was a nanometer-size particleantigen delivery system constructed by combination of the epitope fromthe protective antigen and the plasmid encoding the same epitope. Theepitopes containing 18 lysines which acted as the bridge of the peptideand its control peptide of 18 lysines (18K) were synthesized and puri-fied. The oligonucleotides encoding the epitopes with restrictive en-zyme (RE) Sal I site at 5' terminus and EcoR I site at 3' terminus werealso synthesized and insert into expression plasmidpUMVC1-mGM-CSF. The procedure for preparing PDDV was per-formed by titrating peptide into a solution of the corresponding plasmid.The input molar ratio of peptide to DNA (r) was the ratio of moles oflysine to nucleotide (NH4~+/PO3~-). PDDVs prepared was identified byDNA retardation assay, DNase I digestion assay and electron micros-copy to choose the best condition of preparation. The optimized PDDVswere prepared for the animal experiments.
C57BL/6 mice were divided into 29 groups, 14 mice each group.Each mouse was injected subcutaneously (s.c) in the back with 100μl ofsolution containing 28μg of peptide and 10μg of plasmid pGT or pGrespectively, or PBS (control group). The immunization was repeatedwith 14-day interval. One week after the final vaccination, 6 mice from each group were sacrificed for the detection of the cellular and humoralimmune response. CTL activity of the CD8+ effector cells was assessedin a standard 4-h ~(51)Cr-release assay. T cell proliferation and cytokineswere detected for evaluation of Th cellular immune response. And anti-bodies were measured for evaluation of humoral immune response. Theresults showed that CTL responses, Th response and antibodies wereinduced by the CTL, Th and B-cell epitope-PDDV respectively. But therelevant immune response was not detected in the groups immunizedwith mixed epitope PDDVs.
Two weeks after the last vaccination, 8 mice of each group werechallenged percutaneously with 40 cercariae of S. j aponicum. Six weeksafter challenge, all vaccinated and control mice were sacrificed andperfusion was undertaken with saline containing heparin to recover theadult worms. The livers were digested and the number of eggs was de-termined by microscopic examination. The worm/egg reduction ratewas calculated. After portal perfusion, mice livers were dissected andstained with hematoxylin and eosin (HE) for microscopic examination.The number of egg granulomas was counted and the sizes of noncon-fluent granulomas formed around a single egg containing a maturemiracidium were assessed using a video micrometer. The resultsshowed that several PDDVs induced promising protection. Especially,T3 epitope PDDV induced both cellular and humoral immune responses, achieved 33.8%～44.7% protections against S. japonicum infection anddiminished egg granulomas in the livers of challenged mice.
引文
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