CN114507632A - BCG基因BCG_1246c在制备结核疫苗重组BCG中的应用 - Google Patents
BCG基因BCG_1246c在制备结核疫苗重组BCG中的应用 Download PDFInfo
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- CN114507632A CN114507632A CN202210190916.2A CN202210190916A CN114507632A CN 114507632 A CN114507632 A CN 114507632A CN 202210190916 A CN202210190916 A CN 202210190916A CN 114507632 A CN114507632 A CN 114507632A
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Abstract
本发明提供了一种BCG重组菌ΔBCG_1246c,该BCG重组菌中的基因BCG_1246c被敲除。本发明还提供了该BCG重组菌的制备方法以及其在制备结核疫苗中的应用。本发明提供的BCG重组菌ΔBCG_1246c可以诱导巨噬细胞产生更多的抗菌肽,给予宿主更强的抵抗结核菌感染的能力,有潜力作为结核菌的候选疫苗。
Description
技术领域
本发明涉及生物医药领域,具体涉及BCG基因BCG_1246c在制备结核疫苗重组BCG中的应用。
背景技术
结核病在世界范围是细菌性传染病的主要死亡原因。由于缺乏对成年人肺结核有效的预防性疫苗,全球结核病形势依然严峻。目前唯一获得临床使用许可用于预防结核病的疫苗是卡介苗(Mycobacterium bovisbacille Calmette-Guérin,BCG),这是一种减毒活疫苗。卡介苗于1921年在巴黎首次给新生儿注射1。到 2019年,全球88%的儿童在出生后第一年接受卡介苗接种2。卡介苗对新生儿和学龄儿童的结核性脑膜炎具有70%以上的保护作用3。然而,对成年人肺结核的保护效果非常有限。21世纪初,全球新型结核病疫苗的研发力度不断加大。这些包括Mtb融合蛋白的亚单位佐剂制剂、表达Mtb一种或多种抗原的病毒载体疫苗、灭活分枝杆菌疫苗和减毒分枝杆菌疫苗4,5。
新结核病疫苗的开发遵循两条基本途径6,7。第一种途径是用改良的重组卡介苗(rBCG)或基因敲除减毒的结核分枝杆菌取代卡介苗。基因改良rBCG的特点应该是:a)更安全;b)免疫原性更强;c)诱导更持久的保护;d)对高毒力临床分离株具有保护作用,如结核分枝杆菌北京株、多耐药菌株(MDR)、广泛耐药结核病菌株(XDR)等。重组卡介苗的一种方法是引入卡介苗中缺乏的免疫原性结核菌特异性抗原,如RD1编码的结核抗原基因(ESAT6,CFP10);或者通过过表达卡介苗自身抗原(Ag85复合物的同源物等)。另一种重组卡介苗的方法是对现有卡介苗进行基因编辑,以更好地增强宿主天然免疫反应8。除了这两种rBCG疫苗方法外,另外一种开发结核疫苗的策略是对结核分枝杆菌进行减毒。这包括删除必需的代谢基因以产生营养缺陷型突变体,或主要缺失毒力基因及其调控因子。一项研究表明在田鼠分枝杆菌上表达结核分枝杆菌的RD1抗原显著提高了宿主对结核菌感染的抵抗能力9。还有研究发现重组耻垢分枝杆菌也可以作为结核疫苗。当耻垢分枝杆菌敲除esx-3基因时,可以看到免疫小鼠出现强烈的先天免疫反应。当这种重组耻垢分枝杆菌回转入结核菌的esx-3基因时,在小鼠结核菌攻毒模型中观察到对宿主更好的保护活性。
开发结核病疫苗的第二个主要途径是构建亚单位疫苗。这些疫苗是非活体疫苗,或者以病毒为载体的非复制疫苗。结核病的亚单位疫苗主要是重组蛋白,或使用减毒病毒载体。虽然亚单位疫苗理论上可以用作启动疫苗,但目前主流观点是,它们只能用作辅助卡介苗、重组卡介苗或减毒Mtb疫苗之上的增强疫苗。
目前临床使用的BCG卡介苗对肺结核患者的保护效果有限,构建重组卡介苗是主要研究方向。重组卡介苗的主要研究策略是敲除BCG的毒力基因,激活宿主的免疫应答功能,提高现有疫苗BCG的保护效果。但是哪些基因是BCG 重要的免疫抑制因子尚不明确,以哪个靶点为基础对BCG进行基因编辑可以提高BCG的保护效果还缺少理论基础。
抗菌肽(Antimicrobial Peptides,AMPs)被认为是生物体先天免疫系统的古老防御武器,具有广泛的对抗革兰氏阳性和革兰氏阴性细菌、真菌、寄生虫和病毒的活性。AMPs通常由12-15个氨基酸组成,带有阳离子(由带正电的精氨酸和赖氨酸残基组成)10,其作用机制的是与带负电的菌体膜形成相互作用,从而产生磷脂置换、膜结构紊乱和内部化11。由于AMPs的作用机制不同,因此微生物很少产生耐药性。本发明基于宿主的抗菌肽,寻找显著抑制其表达的BCG毒力基因,为构建效果更好的重组卡介苗提供策略。
发明内容
为了克服现有技术中的缺陷,本发明发现在野生型BCG菌株上缺失毒力基因BCG_1246c构建的重组BCG菌株可以显著提高BCG的免疫保护效果,为结核疫苗开发提供候选,基于此,本发明提供了BCG基因BCG_1246c在制备结核疫苗重组BCG中的应用。
为实现上述目的,本发明采用如下技术方案:
本发明的第一方面是提供一种BCG重组菌ΔBCG_1246c,该BCG重组菌中的基因BCG_1246c被敲除。
进一步地,该BCG重组菌中的基因BCG_1246c通过CRISPR/Cas9技术被敲除。
进一步地,在敲除过程中,采用的BCG_1246c基因gRNA序列为SEQ ID No.: 2。
本发明的第二方面是提供上述BCG重组菌的构建方法,通过CRISPR/Cas9 技术敲除野生型BCG菌株中的基因BCG_1246c获得该BCG重组菌。
本发明的第三方面是提供上述BCG重组菌在制备结核疫苗中的应用,该结核疫苗包含该BCG重组菌。
进一步地,该结核疫苗还包括佐剂。
本发明的第四方面是提供一种结核疫苗重组BCG,为基因BCG_1246c被敲除的卡介苗。
进一步地,BCG_1246c基因通过CRISPR/Cas9技术被敲除。
进一步地,在敲除过程中,采用的BCG_1246c基因gRNA序列为SEQ ID No.: 2。
本发明的第五方面是提供一种BCG菌株BCG_1246c基因敲除载体,该敲除载体是基于CRISPR/Cas9系统的gRNA表达载体,所述gRNA序列为如SEQ ID No.:2所示的序列。
本发明的第六方面是提供上述BCG菌株BCG_1246c基因敲除载体在制备结核疫苗中的应用。
本发明采用以上技术方案,与现有技术相比,具有如下技术效果:
本发明提供的BCG重组菌ΔBCG_1246c可以诱导巨噬细胞产生更多的抗菌肽,给予宿主更强的抵抗结核菌感染的能力,有潜力作为结核菌的候选疫苗。
附图说明
图1显示了本发明一实施例中PCR鉴定BCG_1246c基因敲除菌株的结果;
图2显示了本发明一实施例中ΔBCG_1246c菌株显著促进巨噬细胞抗菌肽基因表达;其中,图A-C分别显示了ΔBCG_1246c菌株对巨噬细胞中Camp, Hamp和Defb3表达量的影响;
图3是本发明一实施例中小鼠免疫攻毒实验的流程图;
图4显示了本发明一实施例中小鼠免疫接种30天后攻毒30天肺组织荷菌量的比较结果;
图5显示了本发明一实施例中免疫接种小鼠感染30天后肺部病理HE染色结果(图A)和抗酸染色结果(图B)。
具体实施方式
本发明提供了BCG基因BCG_1246c在制备抗结核疫苗重组BCG中的应用,其中,基因BCG_1246c(来源数据库: https://www.uniprot.org/uniprot/A0A0H3M5F9)的氨基酸序列为SEQ ID No.:1。
下面通过具体实施例和附图对本发明进行详细和具体的介绍,以使更好的理解本发明,但是下述实施例并不限制本发明范围。
实施例中方法如无特殊说明的采用常规方法,使用的试剂如无特殊说明的使用常规市售试剂或按常规方法配制的试剂。
实施例1
本实施在野生型BCG菌株上构建了BCG_1246c基因缺失菌株,具体的构建过程和结果如下:
在野生型BCG丹麦菌株上利用Cas9技术构建BCG_1246c基因缺失菌株 (ΔBCG_1246c)。
首先制备制BCG:pYC1759的感受态细胞,将pYC1759质粒电转入野生型的BCG丹麦菌株,挑取成功转入质粒的BCG单克隆菌株后在K+的7H9+OADC 培养基中进行菌体扩增,随后进行甘油水洗三次,收集感受态细胞-80度冻存备用。在BCG:pYC1759感受态细胞中电转Cas9以及BCG_1246c基因的sgRNA 表达质粒(其中,BCG_1246c基因gRNA序列为ATCGGCTCCGCATTGAACGC (SEQ ID No.:2)),扩增后涂于K+Zeo抗性培养平板,挑取单克隆后进行PCR 及测序鉴定,结果如图1所示。
实施例2
本实施例在实施例1的基础上,验证ΔBCG_1246c菌株可以诱导巨噬细胞产生更多的抗菌肽,具体的实验步骤和结果如下:
利用小鼠腹腔原代巨噬细胞感染模型,感染野生型BCG菌株和ΔBCG_1246c 菌株(MOI=5)24小时后Trizol裂解细胞,抽提总RNA,反转录为cDNA后通过QPCR对细胞内的Camp,Hamp和Defb3进行定量分析。
如图2所示,BCG敲除BCG_1246c基因后可以显著促进抗菌肽的表达,这提示BCG_1246c基因编码的蛋白可以抑制宿主抗菌肽表达,是BCG的毒力因子。
实施例3
本实施例在动物水平上验证ΔBCG_1246c菌株比BCG菌株具有更强的免疫保护功能,具体的实验步骤和结果如下:
参考图3的流程图,分别给予野生型C57BL/6小鼠尾静脉注射PBS、1×106 CFU的BCG菌株,或者1×106CFU的ΔBCG_1246c菌株。免疫30天后在生物安全三级实验室中给予各组小鼠经呼吸道感染结核菌H37Rv菌株。感染结核菌 30天后颈部脱臼处死小鼠,分离肺组织进行CFU计数,确认各组小鼠肺组织内的荷菌量,同时利用4%的PFA对各组小鼠的肺组织进行固定通过石蜡包埋,组织切片及H&E染色观察各组间肺组织病理改变。
如图4所示,小鼠免疫ΔBCG_1246c菌株相比免疫野生型BCG菌株肺组织荷菌量下降了17.5倍,同时可见更少的中性粒细胞浸润和更多的完好的肺泡组织(如图5)。
综上所述,ΔBCG_1246c菌株比BCG菌株可以更好的保护宿主抵抗结核菌感染。
以上对本发明的具体实施例进行了详细描述,但其只作为范例,本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言,任何对本发明进行等同修改和替代也都在本发明的范畴之中。因此,在不脱离本发明精神和范围下所作的均等变换和修改,都应涵盖在本发明的范围内。
参考文献:
1.Tidjani,O.,Grunitzky,B.,Sadjo,H.&Guérin,N.[The prophylaxis oftuberculosis and vaccination with BCG.A recent study].Ann Pediatr(Paris)39(1992).
2.Chard,A.N.,Gacic-Dobo,M.,Diallo,M.S.,Sodha,S.V.&Wallace,A.S.RoutineVaccination Coverage-Worldwide,2019.MMWR Morb Mortal Wkly Rep69,1706-1710,doi:10.15585/mmwr.mm6945a7(2020).
3.Mangtani,P.et al.Protection by BCG vaccine against tuberculosis:asystematic review of randomized controlled trials.Clin Infect Dis58,470-480,doi:10.1093/cid/cit790(2014).
4.Ginsberg,A.M.Designing tuberculosis vaccine efficacy trials-lessonsfrom recent studies. Expert Rev Vaccines18,423-432,doi:10.1080/14760584.2019.1593143(2019).
5.Ottenhoff,T.H.M.&Kaufmann,S.H.E.Vaccines against tuberculosis:whereare we and where do we need to go?PLoS Pathog8,e1002607,doi:10.1371/journal.ppat.1002607(2012).
6.Kaufmann,S.H.E.Future vaccination strategies against tuberculosis:thinking outside the box.Immunity33,567-577,doi:10.1016/j.immuni.2010.09.015(2010).
7.Ottenhoff,T.H.M.Overcoming the global crisis:"yes,we can",but alsofor TB...?Eur J Immunol39,2014-2020,doi:10.1002/eji.200939518(2009).
8.Reece,S.T.&Kaufmann,S.H.E.Floating between the poles of pathologyand protection: can we pin down the granuloma in tuberculosis?Curr OpinMicrobiol15,63-70, doi:10.1016/j.mib.2011.10.006(2012).
9.Brodin,P.et al.Enhanced protection against tuberculosis byvaccination with recombinant Mycobacterium microti vaccine that induces Tcell immunity against region of difference 1 antigens.J Infect Dis190,115-122(2004).
10.Hancock,R.E.&Lehrer,R.Cationic peptides:a new source ofantibiotics.Trends Biotechnol16,82-88(1998).
11.Lakshmaiah Narayana,J.&Chen,J.-Y.Antimicrobial peptides:Possibleanti-infective agents.Peptides72,88-94,doi:10.1016/j.peptides.2015.05.012(2015)。
序列表
<110> 上海市肺科医院
<120> BCG基因BCG_1246c在制备结核疫苗重组BCG中的应用
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 359
<212> PRT
<213> Mycobacterium bovis
<400> 1
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Ala Gly Gly Phe Gly Thr Ala Ile Ala Ala Ser Glu Pro Ala Tyr Pro
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Trp Ala Pro Gly Pro Pro Pro Ser Pro Ser Pro Val Gly Asp Ala Ser
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Thr Ala Lys Val Val Tyr Ala Leu Gly Gly Ala Arg Met Pro Gly Ile
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Pro Trp Tyr Glu Tyr Thr Asn Gln Ala Gly Ser Gln Tyr Phe Pro Asn
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Ala Lys His Asp Leu Ile Asp Tyr Pro Ala Gly Ala Ala Phe Ser Trp
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Trp Pro Thr Met Leu Leu Pro Pro Gly Ser His Gln Asp Asn Met Thr
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Val Gly Val Ala Val Lys Asp Gly Thr Asn Ser Leu Asp Asn Ala Ile
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His His Gly Thr Asp Pro Ala Ala Ala Val Gly Leu Ser Gln Gly Ser
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Leu Val Leu Asp Gln Glu Gln Ala Arg Leu Ala Asn Asp Pro Thr Ala
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Pro Ala Pro Asp Lys Leu Gln Phe Thr Thr Phe Gly Asp Pro Thr Gly
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Arg His Ala Phe Gly Ala Ser Phe Leu Ala Arg Ile Phe Pro Pro Gly
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Ser His Ile Pro Ile Pro Phe Ile Glu Tyr Thr Met Pro Gln Gln Val
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Asp Ser Gln Tyr Asp Thr Asn His Val Val Thr Ala Tyr Asp Gly Phe
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Ser Asp Phe Pro Asp Arg Pro Asp Asn Leu Leu Ala Val Ala Asn Ala
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Ala Ile Gly Ala Ala Ile Ala His Thr Pro Ile Gly Phe Thr Gly Pro
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Gly Asp Val Pro Pro Gln Asn Ile Arg Thr Thr Val Asn Ser Arg Gly
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Ala Thr Thr Thr Thr Tyr Leu Val Pro Val Asn His Leu Pro Leu Thr
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Leu Pro Leu Arg Tyr Leu Gly Met Ser Asp Ala Glu Val Asp Gln Ile
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Asp Ser Val Leu Gln Pro Gln Ile Asp Ala Ala Tyr Ala Arg Asn Asp
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Asn Trp Phe Thr Arg Pro Val Ser Val Asp Pro Val Arg Gly Leu Asp
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<210> 2
<211> 20
<212> DNA
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atcggctccg cattgaacgc 20
Claims (10)
1.一种BCG重组菌,其特征在于,为ΔBCG_1246c菌株,所述BCG重组菌中的基因BCG_1246c被敲除。
2.根据权利要求1所述的BCG重组菌,其特征在于,所述BCG重组菌中的基因BCG_1246c通过CRISPR/Cas9技术被敲除。
3.根据权利要求2所述的BCG重组菌,其特征在于,在敲除过程中,采用的BCG_1246c基因gRNA序列为SEQ ID No.:2。
4.如权利要求1-3任一项所述的BCG重组菌的构建方法,其特征在于,通过CRISPR/Cas9技术敲除野生型BCG菌株中的基因BCG_1246c获得所述BCG重组菌。
5.如权利要求1-3任一项所述的BCG重组菌在制备结核疫苗中的应用,其特征在于,所述结核疫苗包含所述BCG重组菌。
6.根据权利要求6所述的应用,其特征在于,所述结核疫苗还包括佐剂。
7.一种结核疫苗重组BCG,其特征在于,为基因BCG_1246c被敲除的卡介苗。
8.根据权利要求7所述的结核疫苗重组BCG,其特征在于,BCG_1246c基因通过CRISPR/Cas9技术被敲除;在敲除过程中,采用的BCG_1246c基因gRNA序列优选为SEQ ID No.:2。
9.一种BCG菌株BCG_1246c基因敲除载体,其特征在于,所述敲除载体是基于CRISPR/Cas9系统的gRNA表达载体,所述gRNA序列为如SEQ ID No.:2所示的序列。
10.如权利要求9所述的BCG菌株BCG_1246c基因敲除载体在制备结核疫苗中的应用。
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