CN110251657B - Ebv brlf1及其功能性小肽在抑制炎症小体活性中的应用 - Google Patents
Ebv brlf1及其功能性小肽在抑制炎症小体活性中的应用 Download PDFInfo
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Abstract
本发明公开了BRLF1在制备抑制疱疹病毒激活的炎症小体活性制剂中的应用。本发明中还公开了一种BRLF1功能性小肽,其可作用于炎症小体活性通路,对炎症小体活性具有广谱的抑制作用。通过在小肽偶联穿透信号肽后,具有很好的穿透性,可以直接进入细胞内部,更好发挥抑制炎症小体活性的作用。
Description
技术领域
本发明涉及EBV BRLF1及其功能性小肽在抑制炎症小体活性中的应用。
背景技术
疱疹病毒(Herpesviruses)是一类中等大小的双股DNA病毒,有100种以上成员,其在自然界广泛分布,可感染两栖类(蛙)、禽类(鸡)、哺乳类(兔、马、牛、猪、猫),也能感染灵长类(猴)和人类。根据其理化性质分α、β、γ三个亚科。α疱疹病毒(如单纯疱疹病毒、水痘-带状疱疹病毒)增殖速度快,引起细胞病变。β疱疹病毒(如巨细胞病毒),生长周期长,感染细胞形成巨细胞。γ疱疹病毒(如EB病毒),感染的靶细胞是淋巴样细胞,可引起淋巴增生。疱疹病毒感染的宿主范围广泛,可感染人类和其他脊椎动物。
EB病毒(Epstein-barr virus,EBV)是疱疹病毒家族中的一员,EBV可通过唾液传播,而近年来的一些研究显示这一病毒也能通过性行为传播。目前EBV感染全世界5岁以上人群中95%以上的个体,感染之后,EBV终生存在于携带者体内,呈潜伏感染状态,并可引发多种人类疾病,包括传染性单核细胞增多症(IM)、毛状白斑症、以及实质器官移植后多发的淋巴组织增生性疾病。此外,EBV是最早发现的能导致癌症的病毒,与多种恶性肿瘤相关,如Burkitt淋巴瘤、Hodgkin氏淋巴瘤、非Hodgkin氏淋巴瘤及一些上皮组织癌症(如鼻咽癌、某些形式的胃癌等),广东省作为鼻咽癌的高发地带引发了人们对于EBV的高度关注。
炎症小体系统(inflammasomes)是哺乳动物体内一种重要的固有免疫系统。机体识别自我与非我的第一道防御就是固有免疫,为了准确的检测和迅速的识别并对这些外来刺激做出反应,许多构成宿主防御系统的前线免疫细胞都表达有一种名为模式识别受体(PRR)的特异受体。PRR检测病原相关的分子模式(PAMP)如细菌或病毒成分,继而引发固有免疫应答,包括细胞因子、趋化因子的分泌,免疫细胞的成熟和分化,后者继而引发获得性免疫反应。
前炎症刺激,包括一些PAMP,诱导非活性形式的IL-1β和IL-18前体的表达。这些前体是重要的前炎症细胞因子,它们能够刺激粘附因子和趋化因子的产生,从而引发免疫和炎症反应。非活性的酶原在炎症小体这个大的蛋白复合体的调控下,通过自剪切产生活性的caspase-1的p10/p20二聚体,然后IL-1β和IL-18前体被切割,成熟的炎症因子将被释放到细胞外,而caspase-1的成熟也可能会通过切割GSDMD而导致细胞焦亡的发生。
目前已经研究和分类了部分炎症小体,主要包括NLRP3炎症小体、AIM2炎症小体以及RIG-I炎症小体。在PRR识别特异的PAMP之后,它们作为特异炎症小体复合物的脚手架蛋白,诱导caspase和细胞因子的活化。目前,研究学者们普遍认为,病毒首先激活了炎症小体,然后反过来介导了宿主的抗病毒反应。
虽然近十年来炎症小体的研究取得了较大进展,但是其具体的活化及调控机制还不是很明确,对于在疱疹病毒中,特别是EBV病毒感染诱导和抑制的炎症小体的机制仍然有很多尚待研究的地方。炎症小体在体内的功能和生物学意义仍待进一步阐明,如是否存在活化炎症小体的直接配体,是否有其他类型的炎症小体,吞噬小体破裂和ROS产生的机理等问题都有待研究。随着这些问题的深入研究,将对理解caspase-1活化及IL-1β、IL-18等炎性因子分泌的复杂机制具有重要意义,同时这也为EBV诱导的炎症和感染性疾病的诊治以及相应的药物的研究和开发提供新的思路。
发明内容
本发明的目的在于克服现有技术的不足,提供BRLF1在制备抑制疱疹病毒激活的炎症小体活性制剂中的应用。
本发明的另一个目的在于提供一种BRLF1功能性小肽及其在制备抑制疱疹病毒激活的炎症小体活性制剂中的应用。
本发明所采取的技术方案是:
BRLF1在制备炎症小体活性抑制剂中的应用。
进一步地,炎症小体活性是由疱疹病毒激活的;进一步地,疱疹病毒包括EB病毒(Epstein-barr virus,EBV)、1型单纯疱疹病毒(Herpes simplex virus,HSV-1)。
一种BRLF1功能性小肽,其序列为:PELNEILDTFL(SEQ ID NO:1)或该序列的保守修饰肽。
进一步地,保守修饰肽的个数为1个或2个。
进一步地,BRLF1功能性小肽的一端偶联有穿透信号肽。
进一步地,穿透信号肽的序列为:GRKKRRQRRRPQ-G-KRKK(SEQ ID NO:2)。
上述BRLF1功能性小肽在制备炎症小体活性抑制剂中的应用。
进一步地,炎症小体活性是由疱疹病毒激活的;进一步地,疱疹病毒包括EB病毒(Epstein-barr virus,EBV)、1型单纯疱疹病毒(Herpes simplex virus,HSV-1)。
一种炎症小体活性的抑制剂,其活性成分包括BRLF1或上述的BRLF1功能性小肽,炎症小体活性是由人类或动物疱疹病毒激活的。
进一步地,疱疹病毒包括EB病毒(Epstein-barr virus,EBV)、1型单纯疱疹病毒(Herpes simplex virus,HSV-1)。
本发明的有益效果是:
本发明中提供了BRLF1在制备抑制疱疹病毒激活的炎症小体活性制剂中的应用。
本发明提供了一种BRLF1功能性小肽,其可作用于炎症小体活性通路,对炎症小体活性具有广谱的抑制作用。通过在小肽偶联穿透信号肽后,具有很好的穿透性,可以直接进入细胞内部,更好发挥抑制炎症小体活性的作用。
附图说明
图1:使用炎症小体荧光素酶报告系统检测BRLF1和N572在A549细胞中对HSV-1诱导活化的炎症小体的抑制作用;
图2:western检测BRLF1在THP-1细胞中对HSV-1诱导活化的炎症小体的抑制作用;
图3:ELISA检测BRLF1在THP-1细胞中对HSV-1诱导活化的炎症小体的抑制作用;
图4:western检测BRLF1和N572在THP-1细胞中对HSV-1诱导活化的炎症小体的抑制作用;
图5:western检测N572在THP-1细胞中对HSV-1诱导活化的炎症小体的抑制作用;
图6:western检测N572在p3HR-1细胞中对EBV诱导活化的炎症小体的抑制作用。
具体实施方式
下面结合实验,进一步说明本发明的技术方案。
除非特别说明,本发明采用的试剂、设备和方法为本技术领域常规市购的试剂、设备和常规使用的方法。
EBV作为γ-疱疹病毒,生活周期都分为潜伏期和裂解期,细胞被感染后经过短暂的急性反应后迅速进入潜伏期,在宿主细胞中,EBV的病毒基因组能够持续性的激活宿主的炎症小体系统,使细胞维持一定的炎症小体活化水平。HSV-1作为另一类人类疱疹病毒,主要进行裂解期感染复制,在感染细胞之后能够迅速的通过其病毒基因组和病毒蛋白等活化一系列的炎症小体系统。因此,检测由EBV和HSV-1活化的炎症小体活性可作为评估药物对于病毒诱导的宿主免疫炎症作用的一种手段。
炎症小体活性荧光素酶双报告系统技术如CN104017818A所公开。
本发明中BRLF1的蛋白序列如下所示:
MRPKKDGLEDFLRLTPEIKKQLGSLVSDYCNVLNKEFTAGSVEITLRSYKICKAFINEAKAHGREWGGLMATLNICNFWAILRNNRVRRRAENAGNDACSIACPIVMRYVLDHLIVVTD RFFIQAPSNRVMIPATIGTAMYKLLKHSRVRAYTYSKVLGVDRAAIMASGKQVVEHLNRMEKEGLLSSKFKAFCKWVFTYPVLEEMFQTMVSSKTGHLTDDVKDVRALIKTLPRASYSSHAGQRSYVSGVLPACLLSTKSKAVETPILVSGADRMDEELMGNDGGASHTEARYSESGQFHAFTDELESLPSPTMPLKPGAQSADCGDSSSSSSDSGNSDTEQSEREEARAEAPRLRAPKSRRTSRPNRGQTPCPSNAAEPEQPWIAAVHQESDERPIFPHPSKPTFLPPVKRKKGLRDSREGMFLPKPEAGSAISDVFEGREVCQPKRIRPFHPPGSPWANRPLPASLAPTPTGPVHEPVGSLTPAPVPQPLDPAPAVTPEASHLLEDPDEETSQAVKALREMADTVIPQKEEAAICGQMDLSHPPPRGHLDELTTTLESMTEDLNLDSPLTPELNEILDTFLNDECLLHAMHISTGLSIFDTSLF(SEQ ID NO:3);
偶联穿透信号肽的BRLF1功能性小肽N572的蛋白序列如下所示:
GRKKRRQRRRPQ-G-KRKKPELNEILDTFL(SEQ ID NO:4)。
BRLF1和N572在A549细胞中对HSV-1诱导活化的炎症小体的抑制作用
1)取生长良好的A549细胞,接种于48孔透明平底板中,每孔细胞密度达到75%。使用的培养基是完全培养基:RPMI1640,10%胎牛血清以及1%双抗,培养条件是5%二氧化碳、37℃;
2)贴壁完全后使用Lipo2000转染荧光素酶报告系统(每孔50ng)和BRLF1或N572(每孔250ng);
3)转染6h后换液新鲜RPMI1640完全培养基;
4)换液36h后,换液新鲜无血清RPMI1640培养基,加入HSV-1感染(MOI=1);
5)在感染12h后,取出培养板,取细胞培养基上清20μl,使用荧光素酶报告系统试剂盒检测荧光素酶活性。
结果如图1显示:在A459细胞内,EBV即早期蛋白BRLF1以及基于其开发的小肽N572对由HSV-1活化的炎症小体活性有明显的抑制作用。
BRLF1在THP-1细胞中对HSV-1诱导活化的炎症小体的抑制作用
1)取生长良好的THP-1细胞,接种于6孔透明平底板中。
2)加入BRLF1的慢病毒感染;
3)6h后换液新鲜RPMI1640完全培养基;
4)培养36h后,用TPA诱导12h使其分化为巨噬细胞贴壁;
5)换新鲜RPMI1640完全培养基,加入HSV-1感染(MOI=1),12h后收细胞以及培养基上清并进行蛋白印迹实验和ELISA实验。
实验结果如图2和3所示:在THP-1细胞内BRLF1对HSV-1活化的炎症小体活性有明显的抑制作用。
Western检测BRLF1和N572在THP-1细胞中对HSV-1诱导活化的炎症小体的抑制作用
1)取生长良好的THP-1细胞,接种于6孔透明平底板中,每孔细胞密度达到75%。使用的培养基是完全培养基:RPMI1640,10%胎牛血清以及1%双抗,培养条件是5%二氧化碳、37℃;
2)贴壁完全后使用Lipo2000转染BRLF1或N572(每孔250ng);
3)转染6h后换液新鲜RPMI1640完全培养基;
4)换液36h后,换液新鲜无血清RPMI1640培养基,加入HSV-1感染(MOI=1);
5)在感染12h后,取出培养板,收集细胞进行蛋白印迹实验。
实验结果如图4显示:在THP-1细胞内,EBV即早期蛋白BRLF1以及基于其开发的小肽N572对由HSV-1活化的炎症小体活性有明显的抑制作用。
Western检测N572在THP-1细胞中对HSV-1诱导活化的炎症小体的抑制作用
1)取生长良好的THP-1细胞,接种于6孔透明平底板中。使用的培养基是完全培养基:RPMI1640,10%胎牛血清以及1%双抗,培养条件是5%二氧化碳、37℃;
2)加入HSV-1感染(MOI=1);
3)加入梯度浓度的N572,终浓度分别为0μg/ml、10μg/ml、20μg/ml、50μg/ml、100μg/ml;
4)培养16h后,1000rpm,10min收获细胞;
5)进行蛋白印迹实验。
实验结果如图5显示:在THP-1细胞内N572对HSV-1活化的炎症小体活性有明显的抑制作用,呈一定的浓度依赖性。
Western检测N572在p3HR-1细胞中对EBV诱导活化的炎症小体的抑制作用
1)取生长良好的细胞系p3HR-1,种到6孔板中;
2)加入梯度浓度的N572,终浓度分别为0μg/ml、10μg/ml、20μg/ml、50μg/ml、100μg/ml;
3)培养16h后,1000rpm,10min收获细胞;
4)进行蛋白印迹实验。
实验结果如图6显示:在p3HR-1细胞内N572对EBV活化的炎症小体活性有明显的抑制作用,呈一定的浓度依赖性。
实验发现BRLF1转染处理后的细胞内炎症小体相关蛋白的成熟炎症因子含量明显降低,且细胞外的炎症因子的释放也有明显下降;同时,用N572处理了的含有EBV或HSV-1的细胞内炎症小体相关的成熟炎症因子的含量也明显下降。N572的这些抑制作用呈浓度依赖性,且在较低的浓度就有很好的抑制炎症小体活性的作用,为进一步的抗免疫活化药物研发提供的强有力的理论基础和实践基础,具有重要的研发价值和开发意义。
SEQUENCE LISTING
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Claims (6)
1.BRLF1在制备炎症小体活性抑制剂中的应用,所述炎症小体活性是由EB病毒或1型单纯疱疹病毒激活的。
2.一种BRLF1功能性小肽,其序列为:PELNEILDTFL。
3.根据权利要求2所述的BRLF1功能性小肽,其特征在于:所述BRLF1功能性小肽的一端偶联有穿透信号肽。
4.根据权利要求3所述的BRLF1功能性小肽,其特征在于:所述穿透信号肽的序列为:GRKKRRQRRRPQ-G-KRKK。
5.BRLF1功能性小肽在制备炎症小体活性抑制剂中的应用,其特征在于:所述BRLF1功能性小肽的序列如权利要求2或3所述,所述炎症小体活性是由EB病毒或1型单纯疱疹病毒激活的。
6.一种炎症小体活性的抑制剂,其特征在于:其活性成分包括权利要求2或3所述的BRLF1功能性小肽,所述炎症小体活性是由EB病毒或1型单纯疱疹病毒激活的。
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