CN107177539A - 一种日本血吸虫和破伤风双价口服或滴鼻疫苗 - Google Patents
一种日本血吸虫和破伤风双价口服或滴鼻疫苗 Download PDFInfo
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Abstract
本发明提供了一种芽孢型益生菌粘膜疫苗的构建方法和免疫评价体系,提供了一种能表达病原生物外源性抗原的双转座表达载体和宿主菌,本发明还提供了一种融合表达细胞因子IL‑2的益生菌疫苗载体,本发明还提供了一种日本血吸虫疫苗和破伤风杆菌双价疫苗,以及一种日本血吸虫单价疫苗,所述益生菌疫苗以芽孢型枯草杆菌为口服或滴鼻途径的粘膜递送载体。本发明首次将日本血吸虫Sj26GST和破伤风TTFC等外源基因、细胞因子IL‑2与枯草芽孢粘膜免疫疫苗载体三者有机结合,优势互补。选用Sj26GST和TTFC为模式抗原,利用芽孢载体递送模式抗原,通过芽孢以及芽孢展示的重组IL‑2作为佐剂,调节免疫类型和增强免疫反应水平。
Description
技术领域
本发明涉及一种疫苗,具体涉及一种以IL-2为佐剂,芽孢型益生菌为粘膜递送载体的双价疫苗。
背景技术
使用新一代纳米级生物载体,即枯草杆菌的纳米级芽孢作为粘膜递送载体研发口服或滴鼻疫苗,预计1个月时间的工业生产即可满足高危人群免疫的需求。通过发酵技术生产的芽孢疫苗,比传统鸡胚疫苗培养时间大大缩短,预计每剂量单位成本仅为传统方法生产成本的1/10。因此,研发周期短、生产快、成本低、对外界环境抗干扰能力强、易于储存运输、能产生持久的交叉保护效果、具有佐剂效应的新型疫苗,已成为全世界传染病预防控制的迫切需求。以枯草芽孢杆菌为粘膜疫苗递送载体所构建的疫苗可以满足这些需求。
本发明利用枯草芽孢杆菌内生芽孢构建了多价抗原融合表达体系,选用日本血吸虫26kDa GST(Sj26GST)蛋白为模式抗原和破伤风毒素C片段(TTFC)作为免疫佐剂分子,在芽孢外表面展示(与芽孢CotC外壳蛋白融合表达CotC-Sj26GST-TTFC);并构建与芽孢外表面展示IL-2(与芽孢CotB-IL-2外壳蛋白融合表达)双转构建相结合的方式表达。荧光免疫学实验、激光共聚焦显微镜检测到外源蛋白在芽孢外表面成功地表达,也证明了多价重组抗原的大分子结构不影响芽孢外层蛋白的组装和芽孢形成,同时证明了IL-2能提高疫苗的细胞免疫水平。
合成或重组表达的口服或滴鼻免疫芽孢能引起广效的免疫反应,但诱导的CD8+T细胞免疫水平相对较低。因此本发明利用白细胞介素-2(IL-2)调节免疫类型并增强细胞免疫水平。
白细胞介素(interleukins,ILs)ILs是介导白细胞之间和其他细胞之间相互作用的细胞因子。由淋巴细胞、单核细胞或其它非单个核细胞产生的细胞因子,在细胞间相互作用、疫苗免疫调节、造血以及炎症过程中起重要调节作用。白细胞介素-2(IL-2)主要由CD4+T细胞或CD8+T细胞产生,以自分泌和旁分泌方式发挥效应。主要生物学功能包括:①活化CD4+和CD8+T细胞,促细胞因子产生;②刺激NK细胞增殖、活化,诱导LAK细胞产生;③促活化B细胞增殖及产生抗体;④可激活单核-巨噬细胞。IL-2为人体自身成分,可调节机体的生理过程和提高免疫功能,很低剂量即可发挥作用,疗效显著,副作用小,利用基因工程技术生产的重组细胞因子IL-2作为生物应答调节剂(biologicalresponse modifier,BRM)在治疗感染疾病亦取得了一定疗效,是一种全新的生物制剂,已成为新一代的药物被批准生产。
本发明引入生物应答调节剂IL-2,发挥其免疫调节的佐剂作用,调节免疫反应类型,增强细胞免疫水平,以提高外源重组抗原疫苗的免疫保护效果。
本发明采用的新型纳米级生物载体枯草芽孢杆菌,属革兰氏阳性菌,具有非致病性,分布广泛,通常存在于土壤中,美国食品和药物管理局FDA批准其为“常规安全级”(generally recognized as safe,GRAS),常作为益生菌用于食品或药业。枯草芽孢杆菌在科研和工农业生产领域被广泛应用,具有良好的发酵基础和生产技术,其在相对简单的培养基中就能生长到很高的密度。很多商业用酶都是芽孢杆菌产生的胞外蛋白,例如α-淀粉酶、蛋白酶以及苏云金杆菌的杀虫晶体蛋白等。芽孢杆菌生长迅速、培养条件简单、遗传背景较清楚。芽孢杆菌的芽孢是一种休眠体(图1所示芽孢形成过程),在外界抗性条件下能保持高度的稳定性,包括热稳定性,能抵御恶劣的环境条件。
芽孢这些特性归功于其独特的芽孢衣壳结构,芽孢的衣壳多层结构大约有70多种衣壳蛋白质(Cot proteins)构成(如图2),组成芽孢的内壳、外壳和最外层的皮层crust衣壳层。其中位于最外层的三个衣壳蛋白CotB,CotC和CotG,常用于融合表达外源抗原蛋白或酶,展示于芽孢表面。
枯草芽孢具有独特的免疫学特性,常被用作重组或非重组粘膜疫苗的纳米级生物载体:①芽孢直径约0.6-1.0μm口服或滴鼻免疫,在动物肠道或鼻咽粘膜能被肠道相关淋巴组织(GALT)或者鼻相关淋巴组织(NALT)识别,发挥免疫佐剂作用,活化肠粘膜的相关淋巴组织,增强分泌型(SIgA)抗体的分泌,提高免疫识别能力,并诱导T、B淋巴细胞和巨噬细胞产生细胞因子,通过淋巴细胞再循环而活化全身免疫***,从而增强机体的非特异性和特异性免疫***。②芽孢具有免疫调节的佐剂效应,能诱导产生平衡的Th1/Th2混合型的免疫反应,不仅能激活特异性的体液免疫应答,也能激活特异性的细胞免疫应答。芽孢衣壳展示***被广泛用于表达外源抗原蛋白的重组粘膜疫苗研究;另外,由于其生物粘附性,也被用于吸附型疫苗载体的研究。同时芽孢具有免疫佐剂效应,可用于增强DNA疫苗、多肽疫苗、基因工程蛋白疫苗、灭活病毒颗粒疫苗的免疫效果,从而节约外源蛋白的单次免疫剂量,同时提高免疫保护效果。因此,枯草芽孢杆菌被认为是最具有前景的粘膜疫苗载体,被广泛应用于病原微生物疫苗的研制。
目前,尚未见Sj26GST-TTFC/IL-2-枯草芽孢杆菌重组粘膜疫苗应用的报道。若通过芽孢载体CotB衣壳蛋白融合表达细胞因子IL-2,使其展示于芽孢衣壳表面,与外源性二价抗原基因融合双表达于芽孢表面。这样,既可发挥IL-2的免疫调节作用,增强Th1免疫应答,提高特异性CD8+T细胞免疫水平,又可发挥芽孢的佐剂效应,增强免疫反应的强度。
按照疫苗研制技术,可把疫苗分为传统疫苗和新型疫苗。在新型疫苗的研究使用中,发现仅用基因克隆技术获得的抗原制备出的疫苗不足以取得有效的免疫保护作用。提示真正有效的疫苗不仅依赖于克隆出能诱导具有免疫保护作用的抗原,还有赖于构建优良的载体***,以及研究和评估抗原诱发免疫保护作用的机制和途径。近年来,研究新型疫苗载体,以获得安全、稳定和有效的新型疫苗成为人们关注的热点。用于制备新型疫苗的载体包括重组细菌、重组病毒、DNA载体、RNA载体、树突状细胞、T细胞以及多肽。新型疫苗载体平台的多样化,提供了多种抗原运载方式,也丰富了免疫接种途径,使得在感染部位能产生持久的免疫力,并可根据需要诱导理想的免疫保护类型。因而,新型抗原递呈平台的应用,有望诱导广效持久的免疫保护力,同时缩短疫苗研制和生产时间。
枯草芽孢杆菌作为新型疫苗载体具有独特的优势,被认为是最有前景的粘膜疫苗载体,并开始应用于病原微生物疫苗的研制。Isticato和Mauriello等用破伤风毒素C片段(TTFC,51.8kDa)以及大肠杆菌肠毒素B亚单位(LTB,12kDa)基因tetC和eltB与编码枯草芽孢衣壳蛋白CotB或CotC的基因融合,利用CotB或CotC启动子表达融合蛋白。融合蛋白CotB-TTFC,CotC-TTFC和CotC-LTB在芽孢表面稳定地成功表达,研究显示融合表达并未影响抗原的保护性,也没有破坏芽孢的特性。重组芽孢口服免疫小鼠能引起针对TTFC或LTB的***免疫和局部免疫反应。疫苗评价研究表明,CotB-TTFC芽孢口服免疫小鼠后,血清IgG显著高于对照组,能抵抗20倍TTFC的攻击感染。Hinc等通过融合表达IL-2的芽孢作为免疫佐剂,能调节Th1为主的免疫应答,通过重组融合表达或者吸附外源抗原,产生特异性的细胞免疫反应,对幽门螺杆菌有一定的免疫保护效果。近年随着对芽孢粘附性的认识,枯草芽孢载体在流感和禽流感疫苗研制上有初步探索:Song用灭活得枯草芽孢作为粘膜免疫的佐剂和抗原蛋白载体与H5N1病毒的HA混合吸附,显现出显著的免疫调节佐剂效应,能增强免疫反应水平,并调节以Th1为主的Th1/Th2混合型的免疫反应,对禽流感病毒攻击有保护效果。Guangyu Zhao等通过芽孢衣壳CotB蛋白融合表达流感病毒A的M2e蛋白,口服免疫能产生强效持久的特异性***免疫和粘膜免疫,完全抵抗了流感病毒H1N1的攻击。
传统的疫苗研制技术已经无法满足当今疫苗的需求,必须要将多种新概念、新技术、高效能的疫苗平台互相结合共同实现目标。本发明通过模式抗原、IL-2重组芽孢、枯草芽孢粘膜疫苗平台的综合研究,为日本血吸虫疫苗和破伤风疫苗研发具有持久免疫保护力的口服或滴鼻疫苗提供技术支持和理论依据。
研发周期短,生产成本低,易于储存运输,免疫方式不需注射,能产生持久的交叉保护效果,同时激活体液免疫和细胞免疫,自身具有佐剂效应的新型疫苗,已成为全世界迫切的需求。
发明内容
本发明的目的在于克服现有技术存在的不足之处而提供了一种宿主菌,本发明还提供了一种日本血吸虫及破伤风双价口服或滴鼻疫苗,所述双价疫苗以芽孢型益生菌为粘膜递送载体。
为实现上述目的,所采取的技术方案:本发明提供了一种宿主菌,所述宿主菌通过以下方法制备而成:
(1)将CotB基因启动子序列、CotB编码序列、连接体的核苷酸序列和IL-2的核苷酸序列依次连接到第一表达载体,得到表达cotB-linker-IL2融合蛋白的第一重组表达载体;
(2)在所述步骤(1)中第一重组表达载体***片段外单酶切使得所述第一重组表达载体线性化,然后转化入第一芽孢杆菌感受态细胞,筛选得到表达CotB-linker-IL-2融合蛋白的第一阳性株;
(3)将CotC基因启动子序列、CotC编码序列和上述所述Sj26GST-TTFC的核苷酸序列依次连接到第二表达载体,得到表达CotC-Sj26GST-TTFC融合蛋白的第二重组表达载体;
(4)在所述步骤(3)中第二重组表达载体***片段外单酶切使得所述第二重组表达载体线性化,然后转化入第二芽孢杆菌感受态细胞,筛选得到表达CotC-Sj26GST-TTFC融合蛋白的第二阳性株;
(5)抽提所述步骤(4)中表达CotC-Sj26GST-TTFC融合蛋白的第二阳性株的染色体,转化入由所述步骤(2)中表达IL-2CotB-linker-IL-2融合蛋白的第一阳性株制备的感受态细胞,筛选同时表达CotB-IL2融合蛋白和CotC-Sj26GST-TTFC融合蛋白的阳性克隆,即得所述宿主菌。
优选地,所述连接体的氨基酸序列如SEQ ID NO.1所示。
优选地,所述步骤(3)中Sj26GST-TTFC的核苷酸序列如SEQ ID NO.6所示
优选地,所述步骤(1)中第一表达载体是质粒pDG364,所述步骤(3)中第二表达载体是质粒pDG1664。
优选地,所述步骤(2)中第一芽孢杆菌感受态细胞是枯草芽孢杆菌PY79感受态细胞,所述步骤(4)中第二芽孢杆菌感受态细胞是枯草芽孢杆菌PY79感受态细胞。
本发明提供了上述所述宿主菌在制备日本血吸虫和破伤风双价口服或滴鼻疫苗中的用途。
本发明提供了一种日本血吸虫和破伤风双价口服或滴鼻疫苗,所述日本血吸虫和破伤风双价口服或滴鼻疫苗含有上述所述的宿主菌培养而得的芽孢。
本发明在已构建的益生菌型枯草芽孢杆菌粘膜疫苗平台上,为了诱导以特异性CD8+T细胞为主的免疫反应类型,通过细胞因子IL-2调节增强Th1免疫应答,从而提高特异性CD8+T细胞的免疫反应水平。通过芽孢载体的CotB衣壳蛋白融合表达细胞因子IL-2展示于芽孢衣壳表面,使其发挥佐剂效应,调节免疫应答的类型,增强细胞免疫,预防和彻底清除感染机体的病原微生物;利用芽孢衣壳蛋白CotB融合表达IL-2,获得能够高效激活CD8+T细胞的具有佐剂效应的芽孢株,弥补单纯基因疫苗的不足;利用免疫生物信息学和结构生物学技术设计融合模式基因Sj26GST-TTFC,并通过衣壳蛋白CotC将Sj26GST-TTFC融合表达在已构建的IL-2芽孢株,构建CotB-IL-2/CotC-Sj26GST-TTFC表位双转座重组枯草芽孢疫苗株。构建的重组双价-IL-2-枯草芽孢疫苗株,生产快,成本低,可通过滴鼻或鼻咽喷雾粘膜免疫,为研发具有持久免疫保护力的双价疫苗奠定了技术和理论基础。
本发明的有益效果在于:
本发明立足于发明组在免疫学、病原生物学、生物信息学、分子生物学、流行病学与纳米生物技术等方面良好的研究基础,结合项目组成员在枯草芽孢杆菌粘膜递送疫苗载体和佐剂研究、模式抗原研究、双价疫苗研究上取得的重要进展,***开展枯草芽孢杆菌粘膜递送载体的技术应用于双价疫苗的基础研究。本发明提出的融合表达双价外源抗原基础上,将国际成熟的枯草杆菌的芽孢粘膜免疫递送载体的疫苗研究技术与双价融合表达模式抗原基因技术结合,引用细胞因子IL-2作为免疫调节佐剂分子,实现在病原微生物入侵门户皮肤粘膜等局部产生粘膜免疫,进一步激活***免疫应答,尤其是特异性CD8+T细胞免疫反应,达到交叉免疫保护的效果。枯草杆菌易于基因修饰,生产条件和设备简单,芽孢疫苗适合安全、高效、经济地大批量生产,还具有极好的热稳定性,半衰期长,特别适合现场作为动物的饲料添加疫苗,以及高危人群滴鼻或口服免疫,展现出良好的优势。
具有以下两方面的创新性和优点:
(1)Sj26GST-TTFC双价融合表达抗原序列、细胞因子佐剂IL-2与枯草杆菌的芽孢粘膜疫苗载体技术等多项技术的联合集成与创新。芽孢疫苗载体技术实现了纳米级生物载体对递送抗原的佐剂效应,实现了口服或滴鼻粘膜免疫方式,保障了后续疫苗生产的高效率和保存运输的低成本;细胞因子佐剂IL-2的引入使得调节免疫类型成为可能,促进了特异性CD8+T细胞免疫反应的增强。本项目引入多种技术的联合集成创新,形成了优势互补的有机整体,完善了粘膜免疫疫苗的新技术理论,该方面的研究也属于理论上的创新。
(2)佐剂的创新性设计。本项目发挥新型微生物载体的免疫增强佐剂效应和细胞因子IL-2的免疫调节佐剂效应,将二者的优势互相结合,可以提高疫苗的免疫保护效果,显著降低接种疫苗的剂量和减少免疫次数,为饲料添加型疫苗和特殊人群的免疫接种提供了保障。
本发明具有以下三方面特色:
(1)面向公共卫生的迫切需求,研发高效的口服益生菌型日本血吸虫疫苗和破伤风疫苗,是预防日本血吸虫病和破伤风传播和流行的有效途径。引入疫苗的多种研制技术和佐剂新技术的集成创新,是突出科学理论与实际应用结合的应用性基础研究,能够为国家解决实际问题;
(2)双价口服或滴鼻疫苗可提高群体的免疫力,符合One Health理念。疫苗研发技术,可应用到流感或禽流感疫苗上,针对高危人群,用鼻咽喷雾粘膜免疫,实现高危人群包括家禽从业人员的职业防护免疫,提高群体的免疫力也是阻断新发***禽流感向普通人群传播的有效手段。
(3)枯草杆菌的芽孢为载体的粘膜疫苗,热稳定性好,重组芽孢的构建方式能保护外源性抗原,延长了疫苗的半衰期,易于存储和常温运输,适合发展中国家和不发达地区的实际需求,与传统的疫苗研制方法相比是一种突破,有巨大的研发前景和商业应用价值。
附图说明
图1为枯草芽孢杆菌B.subtilis细胞***及芽孢形成过程(F,forespore内生芽孢;MC,mother cell母细胞;S,spore芽孢;VC,vegetative cell繁殖体细胞.);
图2为枯草杆菌芽孢B.subtilis Spore衣壳蛋白电镜图和结构分布示意图(Daisuke etc,Yakugaku zasshi,2012);
图3为本发明实施例1中cotB-Peptide linker-IL-2融合基因构建示意图;
图4为本发明实施例1中cotC-Sj26GST-TTFC融合基因构建示意图;
图5为本发明实施例1中CotB-IL-2融合表达于芽孢衣壳最外层示意图;
图6为本发明实施例1中CotC-Sj26GST-TTFC表位肽融合表达于芽孢衣壳最外层示意图;
图7为本发明实施例1中将两段外源基因转座到枯草杆菌染色体的示意图;
图8为本发明实施例1中CotB-IL-2与CotC-Sj26GST-TTFC表位肽同时双融合表达于芽孢衣壳最外层示意图;
图9为本发明实施例1中Sj26GST、TTFC和Sj26GST-TTFC阳性克隆PCR鉴定,第1-4泳道分别对应Marker DL10000,Sj26GST、TTFC和Sj26GST-TTFC的PCR产物;
图10为本发明实施例1中重组芽孢阳性克隆PCR鉴定;
图11为本发明实施例1中SDS-PAGE和Western blot分析SjGST、TTFC和SjGST-TTFC蛋白质的表达图;图A,12%SDS-PAGE.分析三个蛋白质的表达.当IPTG诱导表达后(lane3),目的蛋白质(SjGST、TTFC和SjGST-TTFC)均有明显表达,非诱导组作为对照(lane 4).Lane 2为纯化的SjGST、TTFC和SjGST-TTFC蛋白质(箭头所指).图B,Western blot证明蛋白质的表达。Sj26GST,TTFC,Sj26GST-TTFC孵育的一抗分别为小鼠抗Sj26GST血清、小鼠抗TTFC血清,小鼠抗Sj26GST-TTFC血清。二抗均用HRP羊抗小鼠抗体.箭头所指蛋白质大小;
图12为本发明实施例1中免疫荧光和激光共聚焦显微镜检测Sj26GST-TTFC在芽孢外壳的表达。图A所示CotC-Sj26GST-TTFC重组芽孢株的表达。样品和纯化的兔抗TTFC血清孵育,二抗用anti-rabit.IgG-Fluoresceinisothiocyanate(green,FITC;sigma);图B所示重组CotC-Sj26GST-TTFC芽孢与小鼠抗Sj26GST抗体孵育,二抗用anti-mouse IgG-tetramethyl rhodamine isothiocyanate conjugate(red,TRITC;Sigma)。图C所示非重组芽孢野生株PY79做对照;
图13为本发明实施例1中免疫荧光和激光共聚焦显微镜检测IL-12在重组芽孢表面的表达;样品与纯化的小鼠抗IL-2血清孵育,二抗用抗小鼠anti-mouseIgG-tetramethylrhodamine isothiocyanate conjugate(red,TRITC;Sigma)。图a所示重组芽孢株cotB-IL-2在芽孢表面的表达;图b所示非重组野生株PY79作对照;
图14为本发明实施例1中粘膜免疫后抗Sj26GST-TTFC特异性血清IgG的水平变化;
图15本发明实施例1中全脾细胞IFN-γ检测;
图16为本发明实施例1中免疫荧光及流式细胞仪检测;
pUS186-CotC-Sj26GST在芽孢表面的表达;
图17为本发明实施例1中重组芽孢WB600/pUS186-CotC-GST灌胃免疫小鼠后血清Sj26GST特异性IgG水平、IgG1/IgG2a比率及粪便sIgA水平(OD450)。
具体实施方式
为更好的说明本发明的目的、技术方案和优点,下面将结合具体实施例对本发明作进一步说明。
实施例1
本申请发明人在前期研究中以日本血吸虫26kDa GST(Sj26GST)蛋白为模式抗原,利用枯草杆菌表达质粒pUS186将Sj26GST基因构建于枯草杆菌芽孢衣壳基因CotC启动子及其编码序列的下游,在WB600胞外酶缺陷菌株中实现了外源蛋白Sj26GST在芽孢衣壳表面高表达。
利用枯草杆均穿梭整合质粒pDG1664,将CotC-Sj26GST-TTFC通过双交叉置换整合于枯草杆菌染色体,与CotC融合表达于芽孢衣壳外表面;同时利用枯草杆菌穿梭整合质粒pDG364,将CotB-peptide linker-IL-2通过双交叉置换整合于枯草杆菌染色体,与CotB融合表达于芽孢衣壳外表面,实现了利用枯草芽孢杆菌内生芽孢构建了多价抗原融合表达体系。荧光免疫学实验、激光共聚焦显微镜检测到外源蛋白在芽孢外表面成功地表达(图13),同时也证明了多价重组抗原的大分子结构不影响芽孢外层蛋白的组装和芽孢形成。
评估了芽孢的免疫佐剂效应,我们利用分子信息学进行分析并用实验方法检测了芽孢杆菌不同种属的物理化学特性,选择枯草芽孢杆菌PY79,HU58和克劳氏芽孢杆菌O/C作为非重组芽孢-蛋白疫苗的载体与蛋白混合,证实了芽孢对蛋白的吸附作用,用吸附蛋白的芽孢滴鼻免疫小鼠能引起强烈的粘膜免疫反应,在肺组织、粪便、唾液中均能检测到高水平的Sj26GST特异性sIgA的分泌。同时,也能激活小鼠***免疫反应,IgG亚类提示为以Th1占主导的Th1/Th2混合型免疫反应。证实了芽孢作为新型粘膜疫苗佐剂,能提高机体特异性和非特异性免疫水平,并调节免疫反应类型。
研究表明,枯草杆菌芽孢疫苗平台针对特异性病原体能诱导粘膜和***免疫反应,包括特异性CD8+T淋巴细胞的免疫应答,可以有效地防止病原生物的感染,为粘膜疫苗的研发提供理论基础。
1、研究目标
本文利用枯草杆菌内生芽孢构建了多价抗原融合表达体系,选用日本血吸虫26kDa GST(Sj26GST)蛋白为模式抗原和破伤风毒素C片段(TTFC)作为免疫佐剂分子,在芽孢外表面展示(与芽孢CotC外壳蛋白融合表达CotC-Sj26GST-TTFC);并构建与芽孢外表面展示IL-2(与芽孢CotB-IL-2外壳蛋白融合表达)双转构建相结合的方式表达。荧光免疫学实验、激光共聚焦显微镜检测到外源蛋白在芽孢外表面成功地表达,也证明了多价重组抗原的大分子结构不影响芽孢外层蛋白的组装和芽孢形成,同时证明了IL-2能提高疫苗的细胞免疫水平。
2、研究内容
(1)二价模式抗原基因序列的生物信息学分析与基因融合
1)将日本血吸虫26kDa GST(Sj26GST)蛋白为模式抗原和破伤风毒素C片段(TTFC)作为免疫佐剂分子,分析其基因序列,并重组融合Sj26GST-TTFC基因序列
2)重组序列测序检测
3)将重组序列Sj26GST-TTFC构建在芽孢衣壳蛋白CotC基因的C端
4)枯草杆菌芽孢衣壳表面融合表达CotC-Sj26GST-TTFC及融合表达的鉴定
(2)具有佐剂效应的IL-2表达芽孢的构建
1)分析细胞因子IL-2及芽孢衣壳CotB的序列
2)通过连接片断将IL-2构建在芽孢衣壳蛋白CotB基因的C端
3)枯草杆菌芽孢衣壳表面融合表达CotB-IL-2及融合表达的鉴定
(3)重组枯草芽孢疫苗IL-2和Sj26GST-TTFC双表达疫苗株的构建
1)分析芽孢衣壳CotC序列,分析重组融合基因Sj26GST-TTFC序列
2)将融合Sj26GST-TTFC序列构建在CotC基因的C端
3)在IL-2表达芽孢基础上,构建Sj26GST-TTFC芽孢衣壳融合双表达株,即CotB-IL-2/CotC-Sj26GST-TTFC
(4)枯草杆菌芽孢疫苗的生物学活性鉴定及保护性评价
1)重组或非重组疫苗的安全性测定
2)疫苗的免疫学特性研究、免疫水平测定
3)疫苗的保护性攻击实验研究
3、研究方法和实验手段
(1)重组枯草芽孢杆菌疫苗候选株的构建
1)amyE:cotB-IL-2重组枯草芽孢杆菌穿梭整合质粒的构建
从B.subtilis PY79染色体扩增cotB启动子及编码序列的1091bp DNA片段并***质粒pDG364。pDG364在淀粉酶amylase(amyE)位点,携带抗性cat基因及多克隆位点,并能通过amyE基因将携带的cat和***的外源片段整合到B.subtilis染色体。在pDG364-cotB的下游C端,克隆入共457bp人工合成序列:包括具有强大的α螺旋结构的肽链接序列GGGEAAAKGGG(peptide linker)(SEQ ID NO.1)序列和源于Homo sapiens的人IL-2序列,所构建的质粒为pDG364-cotB-linker-IL2,测序鉴定构建是否成功(如图3)。
α螺旋结构的肽链接的基因序列,在引物中直接合成:
linker-gggeaaakggg-F(带Eco RI):
GCC TGT TAG GAA TTC CGC TCC AAT CTC TTT TTA CAA TAG AAT ATA TGG AACCGA AAA TCA TGG CGA TGT ATG AAC GGA TTA GGC C
linker-gggeaaakggg-R(带Bam HI):
CGC GGA TCC TCC TCC ACC TTT CGC TGC TGC TTC TCC TCC ACC GGA TGA TTGATC ATC TGA AG
cotB-linker-IL2序列中,IL2的引物序列:
IL2link-F(带Pcil):
5'-GCT TCA CAT GTT TAC GTC AGT GTA GAG ATG ATA GAT TGG C-3'
IL2link-R(带BamHI):
5'-CAT ATG GAT CCG GTG GAG GAG AAG CAG CAG CG-3'.
2)thrC:cotC-Sj26GST-TTFC重组枯草芽孢杆菌穿梭整合质粒构建
从B.subtilis PY79染色体扩增cotC启动子及编码序列***pDG1664。pDG1664在thrC基因位点,携带有ErmR基因及多克隆位点,并能通过thrC基因将携带的ErmR和***的外源片段整合到B.subtilis染色体。第二步,扩增设计并合成的Sj26GST-TTFC序列,***pDG1664-CotC下游C端,所构建重组质粒为pDG1664-cotC-Sj26GST-TTFC,测序鉴定构建是否成功(如图4)。
表1基因扩增引物
Sj26GST含有一个657bp的最长开放阅读框,起始密码为ATG、终止密码为TGA,编码218个氨基酸。其理论分子量和等电点分别为25.63kDa和6.09。其核苷酸序列如SEQ ID NO:2,氨基酸序列如SEQ ID NO:3所示。
TTFC含有一个1359bp的最长开放阅读框,起始密码为ATG、终止密码为TAA,编码452个氨基酸。其理论分子量和等电点分别为51.77kDa和6.7。其核苷酸序列如SEQ ID NO:4,氨基酸序列如SEQ ID NO:5所示。
Sj26GST-TTFC含有一个2019bp的最长开放阅读框,起始密码为ATG、终止密码为TAA,编码672个氨基酸。其理论分子量和等电点分别为77.4kDa和6.27。其核苷酸序列如SEQID NO:6,氨基酸序列如SEQ ID NO:7所示。
Sj26GST-P1与Sj26GST-P5PCR出来的Sj26GST序列可与TTFC-P3与TTFC-P4引物PCR出来的TTFC序列相链接成Sj26GST-TTFC序列,对应的酶切位点刚好可以***cotC序列下游.
Sj26GST-P1与Sj26GST-P2PCR出来的Sj26GST序列用于单独***PET载体,表达GST蛋白用于制备抗体。
3)IL-2与枯草芽孢衣壳CotB融合表达的构建
将重组质粒pDG364-cotB-linker-IL2***片段外单酶切线性化,并转化PY79感受态细胞,将淀粉酶平板实验阴性的转化子用CmR(5μg/ml)LB平板筛选出阳性克隆,命名为IL-2枯草芽孢株,此株将表达CotB-linker-IL-2融合蛋白。通过流式细胞仪、Western Blot和Dot Blot对融合表达蛋白鉴定及定量分析,通过免疫荧光和激光共聚焦显微镜分析融合蛋白表达于芽孢最外层(如图5)。
4)Sj26GST-TTFC与枯草芽孢衣壳CotC融合表达的构建
将重组质粒pDG1664-cotC-Sj26GST-TTFC***片段外单酶切线性化并转化PY79感受态细胞,将ThrC-阴性转化子用ErmR(1μg/ml)LB平板筛选出阳性克隆,命名为Sj26GST-TTFC枯草芽孢株,此株将表达CotC-Sj26GST-TTFC融合蛋白。通过流式细胞仪、WesternBlot和Dot Blot对融合表达蛋白鉴定及定量分析,通过免疫荧光和激光共聚焦显微镜分析融合蛋白表达于芽孢最外层(如图6)。
5)IL-2与Sj26GST-TTFC双表达菌株的构建(amyE::cotB-IL2;thrC::cotC-Sj26GST-TTFC)
抽提上述构建的重组株Sj26GST-TTFC枯草芽孢株的染色体,转化IL-2重组芽孢株制作的感受态细胞,并用ErmR(1μg/ml)筛选阳性克隆。该双转座重组芽孢株将同时在芽孢衣壳最外层表达CotB-IL2和CotC-Sj26GST-TTFC两种融合蛋白(如图7,8)。通过流式细胞仪、Western Blot和Dot Blot对融合表达蛋白鉴定及定量分析,通过免疫荧光和激光共聚焦显微镜鉴定融合蛋白表达于芽孢最外层。
(4)重组芽孢疫苗的安全性测定
试验动物及分组:无菌Balb/c小鼠,雌雄各半6-8w,每小组20只,设立重组芽孢候选疫苗A组、非重组芽孢候选疫苗B组、空白对照小组,共三组。受试鼠经滴鼻接种芽孢候选疫苗,空白对照组不做任何处理。之后48h内密切观察并记录各组鼠的体温变化、活动量、摄食及饮水次数。在免疫后第3d、第7d及第21d,分别随机处死3只鼠,取注射部位肌肉、心、肝、脾、肺、肾及脑等组织,4%多聚甲醛固定后制作石蜡切片,镜下观察各脏器组织是否出现病理改变。受试鼠于免疫8w后,雌雄混养,使其自然交配。出生后统计和观察幼鼠仔数、畸形仔数、出生后死亡数及发育状况。
(5)疫苗的免疫学特性研究
1)重组芽孢疫苗粘膜免疫效果评价
实验动物及分组:无菌Balb/c小鼠,雌性6-8w,每组6只,设立Naive组、PY79、CotB-IL-2芽孢组、CotC-Sj26GST-TTFC芽孢组、CotB-IL-2/CotC-Sj26GST-TTFC双表达芽孢组、2μg IL-2+2μg Sj26GST-TTFC滴鼻组、2μgSj26GST-TTFC滴鼻组等7组。小鼠经麻醉机用海罗芬(halothane)轻度麻醉后,于第1、22、43d滴鼻滴鼻(Gilson pipette tip,40μl)接种免疫2×109芽孢。在第-1、20、41、62d采集血清、唾液、粪便储存于-20℃备用。末次免疫后即第62d,用CO2处死小鼠,心脏胸腔外扎针取血,开胸取肺和开腹取脾脏。ELISA检测血清特异性IgG及亚类和唾液、粪便、肺组织提取物的特异性sIgA水平;脾脏细胞培养后,进行细胞免疫水平分析:测定脾细胞CD4+和CD8+细胞百分比,检测抗原刺激后,脾脏细胞分泌IFN-γ和TNF-α等细胞因子水平,MTT检测淋巴细胞增殖情况。
3、研究结果
(1)重组pET-28b-SjGST-TTFC质粒的鉴定
挑取转化后的单克隆提取质粒,并以重组质粒为模版,用SjGST、TTFC、SjGST-TTFC特异引物进行PCR,都获得与目的基因大小一致的片段(图9)。阳性克隆测序结果显示,***片段与SjGST、TTFC、SjGST-TTFC基因序列完全一致,表明重组蛋白和融合蛋白基因克隆成功。
(2)重组芽孢阳性克隆PCR鉴定
图10是把get,tetC,gst-tetC这三组基因克隆入了枯草杆菌基因后,培养出的重组枯草杆菌芽孢,直接行菌落PCR检测鉴定是否克隆成功.国际惯例,小写代表基因名称,例如tetC代表基因名称,TTFC大写是对应蛋白质写法。
(3)WB分析重组Sj26GST、TTFC、SjGST-TTFC蛋白免疫原性
使用制备的抗Sj26GST、抗TTFC、抗SjGST-TTFC的小鼠特异性抗血清,Westernblot分析显示三种重组蛋白均能被特异性抗血清识别,表明Sj26GST、TTFC、SjGST-TTFC重组蛋白具有免疫原性和免疫反应性(图11)。
(4)免疫荧光和激光共聚焦显微镜分析Sj26GST-TTFC在重组芽孢表面的展示
如图12所示,免疫荧光和激光共聚焦显微镜显示CotC-Sj26GST–TTFC重组芽孢通过芽孢衣壳蛋白CotC成功展示与芽孢表面.
(5)免疫荧光和激光共聚焦显微镜分析IL-2在重组芽孢CotB-IL-2表面的展示
如图13所示,免疫荧光和激光共聚焦显微镜显示CotB-IL-2在芽孢表面的成功表达。
(6)粘膜免疫后抗Sj26GST-TTFC特异性血清IgG的水平变化
小鼠轻度麻醉后滴鼻免疫各组小鼠。如图14结果清晰显示,CotB-IL2/CotC-Sj26GST-TTFC重组芽孢组,在第21天、第42天检测血清IgG水平显著高于对照组rSj26GST-TTFC组,PY79组和Naive组(P<0.05),
(7)脾细胞分泌的IFN-γ水平
为评估重组芽孢疫苗免疫小鼠后诱导的细胞免疫反应,我们检测脾细胞分泌的IFN-γ水平。如图15数据显示CotB-IL2/CotC-Sj26GST-TTFC重组芽孢滴鼻组(P<0.05)IFN-γ水平显著高于对照组,具有统计学意义。
(8)免疫荧光及流式细胞仪检测pUS186-CotC-Sj26GST在芽孢表面的表达
本发明所列举的在芽孢株WB600中用pUS186载体成功表达的CotC-Sj26GST,用流式细胞仪和免疫荧光显微镜均检测到GST蛋白表达于芽孢外表面(如图16所示)。
(9)重组芽孢WB600/pUS186-CotC-GST灌胃免疫小鼠后血清Sj26GST特异性IgG水平、IgG1/IgG2a比率及粪便sIgA水平(OD450)
重组芽孢CotC-GST口服免疫小鼠后,粪便提取液能检测到特异性抗SjGST的分泌型IgA(sIgA),如上图17中b。结果显示,CotC-SjGST重组芽孢免疫组粪便中特异性sIgA水平显著高于对照组(CotC芽孢组和naive组,P<0.05)。在第16天能检测出sIgA有显著升高,到第33天达到高峰,然而第51天检测粪便sIgA与第33天相比有显著降低(P<0.05)。口服免疫小鼠,检测血清特异性抗SjGST总IgG抗体水平(图17中a),结果显示第二次免疫后第33天和第三次免疫后第51天,CotC-SjGST重组芽孢免疫组特异性IgG显著高于对照组,P<0.05(CotC芽孢免疫组和naive组)。CotC芽孢免疫组和naive组无显著差异,P>0.05。结果表明Sj26GST在枯草杆菌WB600衣壳表面与CotC融合表达,并具有免疫原性,能刺激机体产生***免疫应答。为进一步分析IgG亚型水平,检测Sj26GST特异性IgG1和IgG2a结果显示,免疫后第33天,IgG1和IgG2a均有升高,并且持续升高到第51天(图17中c)。在第16天检测,IgG1抗体水平高出IgG2a抗体水平1.19±0.19倍,但并无显著差异(P>0.05),第二次免疫后,IgG2a水平升高比IgG1抗体水平高出1.28±0.16倍(P>0.05),末次免疫后,第51天,检测到IgG2a持续升高为IgG1水平1.52±0.23倍(P>0.05)。表明第一次免疫后,Th2型免疫反应为主,而第二次、第三次免疫后,以Th1型免疫反应为主,然而并无显著统计学差异,提示CotC-Sj26GST重组芽孢疫苗口服免疫小鼠后,可能产生Th1/Th2混合型免疫反应。
最后所应当说明的是,以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制,尽管参照较佳实施例对本发明作了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和范围。
序列表
<110> 中山大学
<120> 一种日本血吸虫和破伤风双价口服或滴鼻疫苗
<160> 16
<170> PatentIn version 3.3
<210> 1
<211> 11
<212> PRT
<213> 人工序列
<400> 1
Gly Gly Gly Glu Ala Ala Ala Lys Gly Gly Gly
1 5 10
<210> 2
<211> 657
<212> DNA
<213> 人工序列
<400> 2
atgtccccta tactaggtta ttggaaaatt aagggccttg tgcaacccac tcgacttctt 60
ttggaatatc ttgaagaaaa atatgaagag catttgtatg agcgcgatga aggtgataaa 120
tggcgaaaca aaaagtttga attgggtttg gagtttccca atcttcctta ttatattgat 180
ggtgatgtta aattaacaca gtctatggcc atcatacgtt atatagctga caagcacaac 240
atgttgggtg gttgtccaaa agagcgtgca gagatttcaa tgcttgaagg agcggttttg 300
gatattagat acggtgtttc gagaattgca tatagtaaag actttgaaac tctcaaagtt 360
gattttctta gcaagctacc tgaaatgctg aaaatgttcg aagatcgttt atgtcataaa 420
acatatttaa atggtgatca tgtaacccat cctgacttca tgttgtatga cgctcttgat 480
gttgttttat acatggaccc aatgtgcctg gatgcgttcc caaaattagt ttgttttaaa 540
aaacgtattg aagctatccc acaaattgat aagtacttga aatccagcaa gtatatagca 600
tggcctttgc agggctggca agccacgttt ggtggtggcg accatcctcc aaaatga 657
<210> 3
<211> 218
<212> PRT
<213> 人工序列
<400> 3
Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro
1 5 10 15
Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu
20 25 30
Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu
35 40 45
Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys
50 55 60
Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn
65 70 75 80
Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu
85 90 95
Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser
100 105 110
Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu
115 120 125
Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn
130 135 140
Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp
145 150 155 160
Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu
165 170 175
Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr
180 185 190
Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala
195 200 205
Thr Phe Gly Gly Gly Asp His Pro Pro Lys
210 215
<210> 4
<211> 1359
<212> DNA
<213> 人工序列
<400> 4
atgaaaaatc tggattgttg ggttgataat gaagaagata tagatgttat attaaaaaag 60
agtacaattt taaatttaga tattaataat gatattatat cagatatatc tgggtttaat 120
tcatctgtaa taacatatcc agatgctcaa ttggtgcccg gaataaatgg caaagcaata 180
catttagtaa acaatgaatc ttctgaagtt atagtgcata aagctatgga tattgaatat 240
aatgatatgt ttaataattt taccgttagc ttttggttga gggttcctaa agtatctgct 300
agtcatttag aacaatatgg cacaaatgag tattcaataa ttagctctat gaaaaaacat 360
agtctatcaa taggatctgg ttggagtgta tcacttaaag gtaataactt aatatggact 420
ttaaaagatt ccgcgggaga agttagacaa ataactttta gggatttacc tgataaattt 480
aatgcttatt tagcaaataa atgggttttt ataactatta ctaatgatag attatcttct 540
gctaatttgt atataaatgg agtacttatg ggaagtgcag aaattactgg tttaggagct 600
attagagagg ataataatat aacattaaaa ctagatagat gtaataataa taatcaatac 660
gtttctattg ataaatttag gatattttgc aaagcattaa atccaaaaga gattgaaaaa 720
ttatacacaa gttatttatc tataaccttt ttaagagact tctggggaaa ccctttacga 780
tatgatacag aatattattt aataccagta gcttctagtt ctaaagatgt tcaattgaaa 840
aatataacag attatatgta tttgacaaat gcgccatcgt atactaacgg aaaattgaat 900
atatattata gaaggttata taatggacta aaatttatta taaaaagata tacacctaat 960
aatgaaatag attcttttgt taaatcaggt gattttatta aattatatgt atcatataac 1020
aataatgagc acattgtagg ttatccgaaa gatggaaatg cctttaataa tcttgataga 1080
attctaagag taggttataa tgccccaggt atccctcttt ataaaaaaat ggaagcagta 1140
aaattgcgtg atttaaaaac ctattctgta caacttaaat tatatgatga taaaaatgca 1200
tctttaggac tagtaggtac ccataatggt caaataggca acgatccaaa tagggatata 1260
ttaattgcaa gcaactggta ctttaatcat ttaaaagata aaattttagg atgtgattgg 1320
tactttgtac ctacagatga aggatggaca aatgattaa 1359
<210> 5
<211> 452
<212> PRT
<213> 人工序列
<400> 5
Met Lys Asn Leu Asp Cys Trp Val Asp Asn Glu Glu Asp Ile Asp Val
1 5 10 15
Ile Leu Lys Lys Ser Thr Ile Leu Asn Leu Asp Ile Asn Asn Asp Ile
20 25 30
Ile Ser Asp Ile Ser Gly Phe Asn Ser Ser Val Ile Thr Tyr Pro Asp
35 40 45
Ala Gln Leu Val Pro Gly Ile Asn Gly Lys Ala Ile His Leu Val Asn
50 55 60
Asn Glu Ser Ser Glu Val Ile Val His Lys Ala Met Asp Ile Glu Tyr
65 70 75 80
Asn Asp Met Phe Asn Asn Phe Thr Val Ser Phe Trp Leu Arg Val Pro
85 90 95
Lys Val Ser Ala Ser His Leu Glu Gln Tyr Gly Thr Asn Glu Tyr Ser
100 105 110
Ile Ile Ser Ser Met Lys Lys His Ser Leu Ser Ile Gly Ser Gly Trp
115 120 125
Ser Val Ser Leu Lys Gly Asn Asn Leu Ile Trp Thr Leu Lys Asp Ser
130 135 140
Ala Gly Glu Val Arg Gln Ile Thr Phe Arg Asp Leu Pro Asp Lys Phe
145 150 155 160
Asn Ala Tyr Leu Ala Asn Lys Trp Val Phe Ile Thr Ile Thr Asn Asp
165 170 175
Arg Leu Ser Ser Ala Asn Leu Tyr Ile Asn Gly Val Leu Met Gly Ser
180 185 190
Ala Glu Ile Thr Gly Leu Gly Ala Ile Arg Glu Asp Asn Asn Ile Thr
195 200 205
Leu Lys Leu Asp Arg Cys Asn Asn Asn Asn Gln Tyr Val Ser Ile Asp
210 215 220
Lys Phe Arg Ile Phe Cys Lys Ala Leu Asn Pro Lys Glu Ile Glu Lys
225 230 235 240
Leu Tyr Thr Ser Tyr Leu Ser Ile Thr Phe Leu Arg Asp Phe Trp Gly
245 250 255
Asn Pro Leu Arg Tyr Asp Thr Glu Tyr Tyr Leu Ile Pro Val Ala Ser
260 265 270
Ser Ser Lys Asp Val Gln Leu Lys Asn Ile Thr Asp Tyr Met Tyr Leu
275 280 285
Thr Asn Ala Pro Ser Tyr Thr Asn Gly Lys Leu Asn Ile Tyr Tyr Arg
290 295 300
Arg Leu Tyr Asn Gly Leu Lys Phe Ile Ile Lys Arg Tyr Thr Pro Asn
305 310 315 320
Asn Glu Ile Asp Ser Phe Val Lys Ser Gly Asp Phe Ile Lys Leu Tyr
325 330 335
Val Ser Tyr Asn Asn Asn Glu His Ile Val Gly Tyr Pro Lys Asp Gly
340 345 350
Asn Ala Phe Asn Asn Leu Asp Arg Ile Leu Arg Val Gly Tyr Asn Ala
355 360 365
Pro Gly Ile Pro Leu Tyr Lys Lys Met Glu Ala Val Lys Leu Arg Asp
370 375 380
Leu Lys Thr Tyr Ser Val Gln Leu Lys Leu Tyr Asp Asp Lys Asn Ala
385 390 395 400
Ser Leu Gly Leu Val Gly Thr His Asn Gly Gln Ile Gly Asn Asp Pro
405 410 415
Asn Arg Asp Ile Leu Ile Ala Ser Asn Trp Tyr Phe Asn His Leu Lys
420 425 430
Asp Lys Ile Leu Gly Cys Asp Trp Tyr Phe Val Pro Thr Asp Glu Gly
435 440 445
Trp Thr Asn Asp
450
<210> 6
<211> 2019
<212> DNA
<213> 人工序列
<400> 6
atgtccccta tactaggtta ttggaaaatt aagggccttg tgcaacccac tcgacttctt 60
ttggaatatc ttgaagaaaa atatgaagag catttgtatg agcgcgatga aggtgataaa 120
tggcgaaaca aaaagtttga attgggtttg gagtttccca atcttcctta ttatattgat 180
ggtgatgtta aattaacaca gtctatggcc atcatacgtt atatagctga caagcacaac 240
atgttgggtg gttgtccaaa agagcgtgca gagatttcaa tgcttgaagg agcggttttg 300
gatattagat acggtgtttc gagaattgca tatagtaaag actttgaaac tctcaaagtt 360
gattttctta gcaagctacc tgaaatgctg aaaatgttcg aagatcgttt atgtcataaa 420
acatatttaa atggtgatca tgtaacccat cctgacttca tgttgtatga cgctcttgat 480
gttgttttat acatggaccc aatgtgcctg gatgcgttcc caaaattagt ttgttttaaa 540
aaacgtattg aagctatccc acaaattgat aagtacttga aatccagcaa gtatatagca 600
tggcctttgc agggctggca agccacgttt ggtggtggcg accatcctcc aaaaggatcc 660
atgaaaaatc tggattgttg ggttgataat gaagaagata tagatgttat attaaaaaag 720
agtacaattt taaatttaga tattaataat gatattatat cagatatatc tgggtttaat 780
tcatctgtaa taacatatcc agatgctcaa ttggtgcccg gaataaatgg caaagcaata 840
catttagtaa acaatgaatc ttctgaagtt atagtgcata aagctatgga tattgaatat 900
aatgatatgt ttaataattt taccgttagc ttttggttga gggttcctaa agtatctgct 960
agtcatttag aacaatatgg cacaaatgag tattcaataa ttagctctat gaaaaaacat 1020
agtctatcaa taggatctgg ttggagtgta tcacttaaag gtaataactt aatatggact 1080
ttaaaagatt ccgcgggaga agttagacaa ataactttta gggatttacc tgataaattt 1140
aatgcttatt tagcaaataa atgggttttt ataactatta ctaatgatag attatcttct 1200
gctaatttgt atataaatgg agtacttatg ggaagtgcag aaattactgg tttaggagct 1260
attagagagg ataataatat aacattaaaa ctagatagat gtaataataa taatcaatac 1320
gtttctattg ataaatttag gatattttgc aaagcattaa atccaaaaga gattgaaaaa 1380
ttatacacaa gttatttatc tataaccttt ttaagagact tctggggaaa ccctttacga 1440
tatgatacag aatattattt aataccagta gcttctagtt ctaaagatgt tcaattgaaa 1500
aatataacag attatatgta tttgacaaat gcgccatcgt atactaacgg aaaattgaat 1560
atatattata gaaggttata taatggacta aaatttatta taaaaagata tacacctaat 1620
aatgaaatag attcttttgt taaatcaggt gattttatta aattatatgt atcatataac 1680
aataatgagc acattgtagg ttatccgaaa gatggaaatg cctttaataa tcttgataga 1740
attctaagag taggttataa tgccccaggt atccctcttt ataaaaaaat ggaagcagta 1800
aaattgcgtg atttaaaaac ctattctgta caacttaaat tatatgatga taaaaatgca 1860
tctttaggac tagtaggtac ccataatggt caaataggca acgatccaaa tagggatata 1920
ttaattgcaa gcaactggta ctttaatcat ttaaaagata aaattttagg atgtgattgg 1980
tactttgtac ctacagatga aggatggaca aatgattaa 2019
<210> 7
<211> 672
<212> PRT
<213> 人工序列
<400> 7
Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro
1 5 10 15
Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu
20 25 30
Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu
35 40 45
Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys
50 55 60
Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn
65 70 75 80
Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu
85 90 95
Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser
100 105 110
Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu
115 120 125
Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn
130 135 140
Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp
145 150 155 160
Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu
165 170 175
Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr
180 185 190
Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala
195 200 205
Thr Phe Gly Gly Gly Asp His Pro Pro Lys Gly Ser Met Lys Asn Leu
210 215 220
Asp Cys Trp Val Asp Asn Glu Glu Asp Ile Asp Val Ile Leu Lys Lys
225 230 235 240
Ser Thr Ile Leu Asn Leu Asp Ile Asn Asn Asp Ile Ile Ser Asp Ile
245 250 255
Ser Gly Phe Asn Ser Ser Val Ile Thr Tyr Pro Asp Ala Gln Leu Val
260 265 270
Pro Gly Ile Asn Gly Lys Ala Ile His Leu Val Asn Asn Glu Ser Ser
275 280 285
Glu Val Ile Val His Lys Ala Met Asp Ile Glu Tyr Asn Asp Met Phe
290 295 300
Asn Asn Phe Thr Val Ser Phe Trp Leu Arg Val Pro Lys Val Ser Ala
305 310 315 320
Ser His Leu Glu Gln Tyr Gly Thr Asn Glu Tyr Ser Ile Ile Ser Ser
325 330 335
Met Lys Lys His Ser Leu Ser Ile Gly Ser Gly Trp Ser Val Ser Leu
340 345 350
Lys Gly Asn Asn Leu Ile Trp Thr Leu Lys Asp Ser Ala Gly Glu Val
355 360 365
Arg Gln Ile Thr Phe Arg Asp Leu Pro Asp Lys Phe Asn Ala Tyr Leu
370 375 380
Ala Asn Lys Trp Val Phe Ile Thr Ile Thr Asn Asp Arg Leu Ser Ser
385 390 395 400
Ala Asn Leu Tyr Ile Asn Gly Val Leu Met Gly Ser Ala Glu Ile Thr
405 410 415
Gly Leu Gly Ala Ile Arg Glu Asp Asn Asn Ile Thr Leu Lys Leu Asp
420 425 430
Arg Cys Asn Asn Asn Asn Gln Tyr Val Ser Ile Asp Lys Phe Arg Ile
435 440 445
Phe Cys Lys Ala Leu Asn Pro Lys Glu Ile Glu Lys Leu Tyr Thr Ser
450 455 460
Tyr Leu Ser Ile Thr Phe Leu Arg Asp Phe Trp Gly Asn Pro Leu Arg
465 470 475 480
Tyr Asp Thr Glu Tyr Tyr Leu Ile Pro Val Ala Ser Ser Ser Lys Asp
485 490 495
Val Gln Leu Lys Asn Ile Thr Asp Tyr Met Tyr Leu Thr Asn Ala Pro
500 505 510
Ser Tyr Thr Asn Gly Lys Leu Asn Ile Tyr Tyr Arg Arg Leu Tyr Asn
515 520 525
Gly Leu Lys Phe Ile Ile Lys Arg Tyr Thr Pro Asn Asn Glu Ile Asp
530 535 540
Ser Phe Val Lys Ser Gly Asp Phe Ile Lys Leu Tyr Val Ser Tyr Asn
545 550 555 560
Asn Asn Glu His Ile Val Gly Tyr Pro Lys Asp Gly Asn Ala Phe Asn
565 570 575
Asn Leu Asp Arg Ile Leu Arg Val Gly Tyr Asn Ala Pro Gly Ile Pro
580 585 590
Leu Tyr Lys Lys Met Glu Ala Val Lys Leu Arg Asp Leu Lys Thr Tyr
595 600 605
Ser Val Gln Leu Lys Leu Tyr Asp Asp Lys Asn Ala Ser Leu Gly Leu
610 615 620
Val Gly Thr His Asn Gly Gln Ile Gly Asn Asp Pro Asn Arg Asp Ile
625 630 635 640
Leu Ile Ala Ser Asn Trp Tyr Phe Asn His Leu Lys Asp Lys Ile Leu
645 650 655
Gly Cys Asp Trp Tyr Phe Val Pro Thr Asp Glu Gly Trp Thr Asn Asp
660 665 670
<210> 8
<211> 85
<212> DNA
<213> 人工序列
<400> 8
gcctgttagg aattccgctc caatctcttt ttacaataga atatatggaa ccgaaaatca 60
tggcgatgta tgaacggatt aggcc 85
<210> 9
<211> 62
<212> DNA
<213> 人工序列
<400> 9
cgcggatcct cctccacctt tcgctgctgc ttctcctcca ccggatgatt gatcatctga 60
ag 62
<210> 10
<211> 40
<212> DNA
<213> 人工序列
<400> 10
gcttcacatg tttacgtcag tgtagagatg atagattggc 40
<210> 11
<211> 32
<212> DNA
<213> 人工序列
<400> 11
catatggatc cggtggagga gaagcagcag cg 32
<210> 12
<211> 24
<212> DNA
<213> 人工序列
<400> 12
cggctagcat gtcccctata ctag 24
<210> 13
<211> 24
<212> DNA
<213> 人工序列
<400> 13
cccaagcttt cattttggag gatg 24
<210> 14
<211> 28
<212> DNA
<213> 人工序列
<400> 14
cgcggatcca tgaaaaatct ggattgtt 28
<210> 15
<211> 29
<212> DNA
<213> 人工序列
<400> 15
cccaagcttt taatcatttg tccatcctt 29
<210> 16
<211> 23
<212> DNA
<213> 人工序列
<400> 16
cgcggatcct tttggaggat ggt 23
Claims (7)
1.一种宿主菌,其特征在于,所述宿主菌通过以下方法制备而成:
(1)将CotB基因启动子序列、CotB编码序列、连接体的核苷酸序列和IL-2的核苷酸序列依次连接到第一表达载体,得到表达cotB-linker-IL2融合蛋白的第一重组表达载体;
(2)在所述步骤(1)中第一重组表达载体***片段外单酶切使得所述第一重组表达载体线性化,然后转化入第一芽孢杆菌感受态细胞,筛选得到表达CotB-linker-IL-2融合蛋白的第一阳性株;
(3)将CotC基因启动子序列、CotC编码序列和外源性模式基因Sj26GST-TTFC的核苷酸序列依次连接到第二表达载体,得到表达CotC-Sj26GST-TTFC融合蛋白的第二重组表达载体;
(4)在所述步骤(3)中第二重组表达载体***片段外单酶切使得所述第二重组表达载体线性化,然后转化入第二芽孢杆菌感受态细胞,筛选得到表达CotC-Sj26GST-TTFC融合蛋白的第二阳性株;
(5)抽提所述步骤(4)中表达CotC-Sj26GST-TTFC融合蛋白的第二阳性株的染色体,转化入由所述步骤(2)中表达IL-2CotB-linker-IL-2融合蛋白的第一阳性株制备的感受态细胞,筛选同时表达CotB-IL2融合蛋白和CotC-Sj26GST-TTFC融合蛋白的阳性克隆,即得所述宿主菌。
2.根据权利要求1所述的宿主菌,其特征在于,所述连接体的氨基酸序列如SEQ IDNO.1所示。
3.根据权利要求1所述的宿主菌,其特征在于,所述步骤(3)中Sj26GST-TTFC的核苷酸序列如SEQ ID NO.6所示。
4.根据权利要求1所述的宿主菌,其特征在于,所述步骤(1)中第一表达载体是质粒pDG364,所述步骤(3)中第二表达载体是质粒pDG1664。
5.根据权利要求1所述的宿主菌,其特征在于,所述步骤(2)中第一芽孢杆菌感受态细胞是枯草芽孢杆菌PY79感受态细胞,所述步骤(4)中第二芽孢杆菌感受态细胞是枯草芽孢杆菌PY79感受态细胞。
6.如权利要求1所述宿主菌在制备日本血吸虫和破伤风双价口服或滴鼻疫苗中的用途。
7.一种日本血吸虫和破伤风双价口服或滴鼻疫苗,其特征在于,所述日本血吸虫和破伤风双价口服或滴鼻疫苗含有由权利要求1-4任一所述的宿主菌培养而得的芽孢。
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