CN112851770B - 一种用于诊断或防治金黄色葡萄球菌感染的α溶血素抗原表位肽及其应用 - Google Patents
一种用于诊断或防治金黄色葡萄球菌感染的α溶血素抗原表位肽及其应用 Download PDFInfo
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Abstract
本发明公开了本发明提供了一种用于诊断或防治金黄色葡萄球菌感染的抗原表位肽，包含氨基酸序列为SEQ ID NO:1的多肽，本发明还提供了该抗原表位肽在制备用于诊断、预防或治疗金黄色葡萄球菌感染中的应用。本发明通过筛选确定了金黄色葡萄球菌溶血素α的抗体优势表位肽，具有较强的免疫原性，同时该优势表位肽的氨基酸序列在多种S.aureus菌株中序列保守，因此，也可用于制备金黄色葡萄球菌感染的诊断试剂，或用于其他S.aureus感染的预防或治疗。
Description
技术领域
本发明涉及医疗诊断技术领域，具体涉一种用于诊断或防治金黄色葡萄球菌感染的抗原表位肽及其应用。
背景技术
金黄色葡萄球菌(Staphylococcus aureus，S.aureus)作为革兰氏阳性菌的代表，是一类在自然界广泛存在的致病性球菌，也是引起医院感染和社区感染的一种重要致病菌。调查研究表明，在美国，社区皮肤及软组织感染最常见的病原菌为S.aureus(约占75％)；在日本，脓疱病中S.aureus引发的大疱性脓疱病占的92％；在非洲，热带脓性肌炎病原体中S.aureus占55-72％；在中国，感染性心内膜炎的头号致病菌为S.aureus(占31-34％)。此外，S.aureus感染以急性、化脓性为特征，局部可引起皮肤和软组织等的化脓性感染，经久不愈；全身可导致骨髓炎、脓毒性关节炎、心内膜炎、肺炎、脓毒血症等严重感染及并发症，死亡率高达20％。同时，金黄色葡萄球菌的外毒素还可引起食物中毒、烫伤样皮肤综合征和中毒性休克综合征等全身致死性感染。
对于金黄色葡萄球菌感染的治疗，通常选用红霉素、新型青霉素、庆大霉素、万古霉素或先锋霉素VI等抗生素。但是由于多重耐药金黄色葡萄球菌的出现，目前用单一抗生素治疗金黄色葡萄球菌感染已经越来越困难。临床数据显示，具有多重抗生素耐药性的金黄色葡萄球菌在社区金黄色葡萄球菌感染中占到60％，而在医院这一比例占到80％。其中特别突出的是甲氧西林耐药的金黄色葡萄球菌菌株(methicillin-resistant S.aureus,MRSA)，2009年欧洲9个国家MRSA占到临床金黄色葡萄球菌株的25-50％。MRSA导致的感染用抗生素疗法难以治愈并且有很高的致死率。2018年中国MRSA全国平均检出率为35.0％，居革兰阳性耐药菌首位。MRSA侵袭性感染所致菌血症，90天内死亡率超过50％。目前临床主要的抗生素治疗已无力控制MRSA感染，疫苗研制迫在眉睫。
MRSA致病力强弱主要取决于其产生的毒素和侵袭酶的能力，其中溶血素α(alpha-Hemolysin，Hla)也是金葡菌感染致病的重要外毒素，通常由致病性金葡菌特别是MRSA产生，Hla可通过促使中性粒细胞裂解、损害上皮细胞，引起菌血症等临床症状，Hla免疫可缓解MRSA流行株所致的皮肤、软组织坏死及肺炎。通过Blast比对分析，Hla基因序列在已公布的致病性金黄色葡萄球菌中具有高度的保守性，其基因同源性大于90％，因此是理想的疫苗候选抗原。但由于Hla溶血活性强，直接作为疫苗组分可能存在安全性问题。研究证实，第35位的组氨酸(His)在穿孔复合物形成中具有重要作用，对该氨基酸进行定点突变为亮氨酸(Leu)后，可大大降低Hla的溶血活性。因此，本品中的Hla组分为经突变获得的突变子HlaH35L，除了降低溶血活性外未发现其他生物学功能改变。
在MRSA的疫苗应答中，抗体应答起主要保护作用。研究证实，不能产生抗毒素中和抗体的人更易发生葡萄球菌感染相关的毒性休克综合征。由于蛋白抗原发挥其功能主要通过表位来体现特异性。因此，Hla抗原中免疫优势应答的保护性表位的鉴定，是提升和优化基于Hla抗原的金黄色葡萄球菌疫苗设计的重要前提。筛选Hla的免疫优势表位，是激发更有效的Hla免疫应答的前提。目前的已知的Hla的B细胞表位，或通过生物信息学软件推测，或通过单克隆抗体鉴定，或使用人或动物免疫模型中鉴定，该方法均无法鉴定临床MRSA感染状态下的人群免疫优势表位。尚未有全面筛选临床MRSA感染状态，参与免疫应答的Hla的优势表位的报道。因此，建立一种准确有效的筛选及鉴定临床MRSA感染状态下，参与免疫应答的Hla的B细胞优势表位的方法显得尤为重要。
发明内容
本发明的目的是为了解决现有技术存在的上述问题，提供了一种金黄色葡萄球菌溶血素α的抗体优势表位肽，以及该表位肽在制备用于诊断、预防和/或治疗金黄色葡萄球菌感染的药物中的应用。
本发明提供了一种用于诊断或防治金黄色葡萄球菌感染的α溶血素抗原表位肽，包含氨基酸序列为SEQ ID NO：1(KVIFNNMVNQNW)的多肽。
在根据本发明的一个实施方案中，所述α溶血素抗原表位肽为氨基酸序列为SEQID NO：29或SEQ ID NO：30的多肽。
在根据本发明的一个实施方案中，还包含偶联在所述多肽N端或C端的多肽标记。
在根据本发明的一个实施方案中，所述多肽标记为生物素标记或荧光标记。
本发明还提供了一种用于制备抗金黄色葡萄球菌的抗体的融合蛋白，所述融合蛋白包含载体蛋白和上述的α溶血素抗原表位肽；所述载体蛋白选自匙孔血蓝蛋白(KLH)、牛血清白蛋(BSA)、甲状腺球蛋白、纤维蛋白原、明胶、多聚抗原肽中的一种；优选地，所述多聚抗原肽为多聚赖氨酸(PLL)。
本发明还提供了上述α溶血素抗原表位肽在制备用于诊断、预防或治疗金黄色葡萄球菌感染的药物中的应用。所述金黄色葡萄球菌可以为任意的能够引起感染的金黄色葡萄球菌，特别是耐药性极强的甲氧西林耐药的金黄色葡萄球菌菌株，所述甲氧西林耐药的金黄色葡萄球菌菌株可以为MRSA252标准株。
本发明进一步提供了一种用于金黄色葡萄球菌感染的诊断试剂，包含上述的抗原表位肽。
在根据本发明的一个实施方案中所述α溶血素抗原表位肽，包被于检测载体上，所述检测载体选自聚苯乙烯微量反应板、胶体金试剂条、磁珠和微流控芯片中的任一种。
在根据本发明的一个实施方案中，还包含特异性识别人IgG抗体的第二抗体；例如，用免疫优势表位肽—KLH(钥孔血蓝蛋白)偶联物融合蛋白免疫动物，分析该优势表位肽的免疫原性与免疫反应性。
优选地，所述第二抗体选自兔抗人单克隆抗体、兔抗人多克隆抗体、鼠抗人单克隆抗体、鼠抗人多克隆抗体、羊抗人多克隆抗体或羊抗人多克隆抗体中的一种；
优选地，所述第二抗体偶联有激活或猝灭所述特异性荧光基团的配合基团。
本发明的另一方面提供了上述的抗原表位肽在制备用于预防和/或治疗金黄色葡萄球菌感染的药物中的应用。所述药物可以被制备成不同的剂型而通过不同的途径进行给药，优选的，为了避免所述疫苗中抗原成分的降解，所述疫苗被制备成用于静脉给药的剂型，例如，可以为针剂。
本发明进一步提供了一种用于预防或治疗金黄色葡萄球菌感染的药物，其包含上述的α溶血素抗原表位肽。
在根据本发明的一个实施方案中，所述佐剂选自Quil-A佐剂(购自InvivoGen公司)
本发明的有益效果是：
本发明提供的金黄色葡萄球菌溶血素α的抗体优势表位肽均能在动物体内诱发高水平优势表位抗血清，可以用于制备预防金黄色葡萄球菌感染的高效、低毒、高安全性的基于Hla的药物，如预防型疫苗。
本发明提供的金黄色葡萄球菌溶血素α的抗体优势表位肽具有较强的免疫原性，用该优势表位免疫动物，免疫制剂无无关成分或有害成分，以该优势表位肽制备的特异性单克隆抗体可以较好地的预防金黄色葡萄球菌感染。
经序列比对分析，本发明提供的金黄色葡萄球菌溶血素α的抗体优势表位肽在多种S.aureus菌株中序列保守，因此，其也可用作金黄色葡萄球菌感染的诊断试剂或用于对其他S.aureus感染的预防和治疗。
附图说明
图1为使用人群的MRSA阳性抗血清作为一抗对本发明筛选到的重叠肽进行ELISA检测的结果图谱；
图2为本发明筛选到的免疫优势表位肽免疫小鼠获得的抗血清与Hla表位肽的结合能力分析结果图谱；
图3为本发明筛选到的免疫优势表位肽Hla162-179、Hla168-185的KLH融合蛋白经主动免疫减轻小鼠肾脏及肺脏金黄色葡萄球菌的定植的能力检测图谱；
图4为本发明筛选到的抗体免疫优势表位肽Hla162-179、Hla168-185在Hla三维结构中的位置分布分析结果图谱；
图5为本发明筛选到的抗体免疫优势表位肽Hla162-179、Hla168-185的氨基酸序列保守性分析结果图谱。
具体实施方式
下面对本发明的较佳实施例进行详细阐述，以使本发明的优点和特征能更易被本领域人员理解，从而对本发明的保护范围做出更为清楚明确的界定。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1重叠肽的获得
以Hla蛋白序列(Sequence ID：ADQ77533.1)为基础，相对于预期的重叠肽的长度，每次向下游移动小于重叠肽的长度的氨基酸个数，再次获得另一条预期的重叠肽。其中，预期的重叠肽的长度可以为15-30个氨基酸，每次步移的氨基酸个数可以为4-8个，本实施例中从第1号氨基酸开始，每次步移6个氨基酸，合成步移重叠的18个氨基酸多肽(上海强耀生物科技有限公司)，共得到47条重叠肽。纯度均大于95％。合成的步移重叠肽信息如表1所示。将合成肽段用二甲亚砜(DMSO)溶解至1mg/mL的储存浓度，分装后-70℃冻存，临用时用PBS稀释成1mM。
表1步移重叠肽
实施例2临床MRSA阳性血清的收集和保存
用临床签署知情同意书的MRSA阳性血清人群(25位18-64岁金葡菌感染者)测抗血清效价，选择Hla效价大于1：64000的临床MRSA阳性血清用于后续检测。
实施例3 Hla的B细胞免疫优势表位的筛选
调整重叠肽包被浓度15μg/孔(以全蛋白Hla(Sequence ID：ADQ77533.1)为阳性对照)，对孔板进行包被-洗涤-封闭-再次洗涤后，加入实施例2获得的Hla免疫抗血清，稀释度为1∶300，孵育1.5h-洗涤后，加入HRP-羊抗小鼠IgG(购自恩晶生物，货号E1WP319)，稀释度为1∶3500，洗涤后加入TMB底物显色液(购自Beyotime/碧云天，货号P0209-100ml)，终止反应后在450nm处读OD值，按照公式18氨基酸重叠肽OD检测值-空白对照检测值)/(阴性肽OD检测值-空白对照检测值)≥2.1为阳性重叠肽。经SPSS16.0数据检验，获得相对于其他阳性重叠肽读数具有显著统计学意义的阳性重叠肽，定义为B细胞的免疫优势表位肽，也即免疫优势表位肽。
结果如图1所示：有2个阳性重叠肽Hla162-179(SEQ ID NO：29DKKVGWKVIFNNMVNQNW)、Hla168-185(SEQ ID NO：30 KVIFNNMVNQNWGPYDRD)，与其他优势表位肽读数具有显著统计学意义，定义为免疫优势表位，该图中OVA192-201为阴性无关肽。该方法不仅筛选出了Hla的所有免疫应答的B细胞表位，而且明确了Hla的B细胞免疫优势表位肽。
实施例4 Hla的优势表位肽的免疫原性及免疫反应性鉴定
将实施例3鉴定到的Hla的B细胞免疫优势表位肽与KLH(血蓝蛋白)等浓度偶联(委托上海吉尔生化有限公司完成)，得到融合蛋白，表位肽-KLH融合蛋白以60μg/只，Quil-A佐剂(购自InvivoGen公司)剂量以10ug/只，混合后于0、14、21天经BALB/c小鼠(10只，6-8周龄)大腿肌注免疫，末次免疫7天后取小鼠眼球血，分离抗血清，测抗血清效价，分装后-70℃冻存。
抗血清与优势表位肽的结合的检测：调整Hla优势表位肽包被浓度为15μg/孔，包被-洗涤-封闭-再次洗涤后，加入稀释度分别为1∶50，1∶100，1∶200，1∶400，1∶800，1∶1600，1∶3200，1∶6400，1∶12800，1∶25600及1∶51200的抗血清(正常小鼠血清作阴性对照，PBS为空白对照)，孵育1.5h-洗涤后，加入HRP-羊抗小鼠IgG(购自恩晶生物，货号E1WP319)，的稀释度为1∶3500，洗涤后加入TMB底物显色液购自Beyotime/碧云天，货号P0209-100ml)，终止反应后在450nm处读OD值。
结果如图2所示：Anti-Hla162-179-KLH免疫小鼠的优势表位肽的抗血清平均效价为1：22400，Anti-Hla168-185-KLH免疫小鼠的优势表位肽的抗血清平均效价分别为1：12800。以抗血清稀释度为横坐标，以450nm处OD值为纵坐标，可见Hla优势表位肽特异性抗血清在对应效价时，均能较强地与Hla表位肽结合。
实施例5免疫优势表位肽主动免疫减轻小鼠肾脏及肺脏金黄色葡萄球菌的定植的能力检测
免疫优势表位肽-KLH融合蛋白在Qui-A佐剂(购自)辅助下于第0，14，21天经三次肌注免疫6-8周BALB/c小鼠，末次免疫后第7天，尾静脉注射亚致死剂量MRSA252标准株(购自ATCC美国模式培养物菌种资源库，6×108CFU/ml)感染小鼠。在攻毒的第48小时，采集小鼠肾脏及肺脏组织，检测每只小鼠脏器细菌定植数量，评价该优势表位肽特异性单克隆抗体对小鼠的主动免疫保护效果。同时，设置PBS未主动免疫对照组。金黄色葡萄球菌定植量的检测：脱颈椎处死BALB/c小鼠，75％酒精消毒，无菌取组织标本称重，置于2ml无菌的PBS中，于洁净的玻璃匀浆器中进行匀浆，取1ml均浆按照1∶10，1∶100，1∶1000比例进行稀释，每稀释度各取100μL轻轻涂布于固体培养基上，置于37℃，培养24h，做菌落计数(CFU/ml)，并行革兰氏染色典型的镜下形态和PCR检测以证实为金黄色葡萄球菌。
结果如图3所示，结果显示：与PBS组为对照，Hla168-185-KLH主动免疫能显著减轻小鼠肾脏和肺脏的MRSA252定植数量，P值有统计学差异(*表示P＜0.05，**表示P＜0.001)。而Hla162-179-KLH主动免疫并未获得显著的清除脏器细菌的效果。证实，Hla168-185为抗MRSA252标准菌株感染的保护性免疫优势表位。
实施例6
本实施例用于说明抗体免疫优势表位肽在Hla全蛋白三维结构中的位置分布分析结果
在PubMed蛋白公开数据库下载已报道Hla蛋白的3D结构图，用PyMOL 1.1 program软件标注实验中筛选出的免疫优势表位肽的序列位置。
结果如图4所示，该优势肽Hla162-179、Hla168-185分别位于Hla三维晶体结构的β片层和loop区，可见，该优势表位肽序列(抗体优势表位)是Hla表位疫苗的可靠候选分子。
实施例7
本实施例用于本发明筛选到的抗体免疫优势表位肽Hla162-179、Hla168-185的氨基酸序列保守性分析结果。
在Genbank数据库检索36株金黄色葡萄球菌的Hla蛋白的氨基酸序列，用NCBI的Basic Local Alignment Search Tool(BLAST)软件进行氨基酸序列比对分析，随机选择36株菌株进行多序列比对(Multiple Alignment)，网站地址为https：//blast.ncbi.nlm.nih.gov/Blast.cgi。
结果如图5所示，该优势肽Hla162-179、Hla168-185在36种金黄色葡萄球菌各菌株中的氨基酸序列保守，因此具有良好的应用前景。
上述发明内容及具体实施方式意在证明本发明所提供技术方案的实际应用，不应解释为对本发明保护范围的限定。本领域技术人员在本发明的精神和原理内，当可作各种修改、等同替换、或改进。本发明的保护范围以所附权利要求书为准。
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<110> 中国人民解放军陆军军医大学
<120> 一种用于诊断或防治金黄色葡萄球菌感染的α溶血素抗原表位肽及其应用
<141> 2021-02-05
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<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 4
Thr Asp Ile Gly Ser Asn Thr Thr Val Lys Thr Gly Asp Leu Val Thr
1 5 10 15
Tyr Asp
<210> 5
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 5
Thr Thr Val Lys Thr Gly Asp Leu Val Thr Tyr Asp Lys Glu Asn Gly
1 5 10 15
Met Leu
<210> 6
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 6
Asp Leu Val Thr Tyr Asp Lys Glu Asn Gly Met Leu Lys Lys Val Phe
1 5 10 15
Tyr Ser
<210> 7
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 7
Lys Glu Asn Gly Met Leu Lys Lys Val Phe Tyr Ser Phe Ile Asp Asp
1 5 10 15
Lys Asn
<210> 8
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 8
Lys Lys Val Phe Tyr Ser Phe Ile Asp Asp Lys Asn His Asn Lys Lys
1 5 10 15
Ile Leu
<210> 9
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 9
Phe Ile Asp Asp Lys Asn His Asn Lys Lys Ile Leu Val Ile Arg Thr
1 5 10 15
Lys Gly
<210> 10
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 10
His Asn Lys Lys Ile Leu Val Ile Arg Thr Lys Gly Thr Ile Ala Gly
1 5 10 15
Gln Tyr
<210> 11
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 11
Val Ile Arg Thr Lys Gly Thr Ile Ala Gly Gln Tyr Arg Val Tyr Ser
1 5 10 15
Glu Glu
<210> 12
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 12
Thr Ile Ala Gly Gln Tyr Arg Val Tyr Ser Glu Glu Gly Ala Asn Lys
1 5 10 15
Ser Gly
<210> 13
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 13
Arg Val Tyr Ser Glu Glu Gly Ala Asn Lys Ser Gly Leu Ala Trp Pro
1 5 10 15
Ser Ala
<210> 14
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 14
Gly Ala Asn Lys Ser Gly Leu Ala Trp Pro Ser Ala Phe Lys Val Gln
1 5 10 15
Leu Gln
<210> 15
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 15
Leu Ala Trp Pro Ser Ala Phe Lys Val Gln Leu Gln Leu Pro Asp Asn
1 5 10 15
Glu Val
<210> 16
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 16
Phe Lys Val Gln Leu Gln Leu Pro Asp Asn Glu Val Ala Gln Ile Ser
1 5 10 15
Asp Tyr
<210> 17
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 17
Leu Pro Asp Asn Glu Val Ala Gln Ile Ser Asp Tyr Tyr Pro Arg Asn
1 5 10 15
Ser Ile
<210> 18
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 18
Ala Gln Ile Ser Asp Tyr Tyr Pro Arg Asn Ser Ile Asp Thr Lys Glu
1 5 10 15
Tyr Met
<210> 19
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 19
Tyr Pro Arg Asn Ser Ile Asp Thr Lys Glu Tyr Met Ser Thr Leu Thr
1 5 10 15
Tyr Gly
<210> 20
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 20
Asp Thr Lys Glu Tyr Met Ser Thr Leu Thr Tyr Gly Phe Asn Gly Asn
1 5 10 15
Val Thr
<210> 21
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 21
Ser Thr Leu Thr Tyr Gly Phe Asn Gly Asn Val Thr Gly Asp Asp Ser
1 5 10 15
Gly Lys
<210> 22
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 22
Phe Asn Gly Asn Val Thr Gly Asp Asp Ser Gly Lys Ile Gly Gly Leu
1 5 10 15
Ile Gly
<210> 23
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 23
Gly Asp Asp Ser Gly Lys Ile Gly Gly Leu Ile Gly Ala Asn Val Ser
1 5 10 15
Ile Gly
<210> 24
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 24
Ile Gly Gly Leu Ile Gly Ala Asn Val Ser Ile Gly His Thr Leu Lys
1 5 10 15
Tyr Val
<210> 25
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 25
Ala Asn Val Ser Ile Gly His Thr Leu Lys Tyr Val Gln Pro Asp Phe
1 5 10 15
Lys Thr
<210> 26
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 26
His Thr Leu Lys Tyr Val Gln Pro Asp Phe Lys Thr Ile Leu Glu Ser
1 5 10 15
Pro Thr
<210> 27
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 27
Gln Pro Asp Phe Lys Thr Ile Leu Glu Ser Pro Thr Asp Lys Lys Val
1 5 10 15
Gly Trp
<210> 28
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 28
Ile Leu Glu Ser Pro Thr Asp Lys Lys Val Gly Trp Lys Val Ile Phe
1 5 10 15
Asn Asn
<210> 29
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 29
Asp Lys Lys Val Gly Trp Lys Val Ile Phe Asn Asn Met Val Asn Gln
1 5 10 15
Asn Trp
<210> 30
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 30
Lys Val Ile Phe Asn Asn Met Val Asn Gln Asn Trp Gly Pro Tyr Asp
1 5 10 15
Arg Asp
<210> 31
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 31
Met Val Asn Gln Asn Trp Gly Pro Tyr Asp Arg Asp Ser Trp Asn Pro
1 5 10 15
Val Tyr
<210> 32
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 32
Gly Pro Tyr Asp Arg Asp Ser Trp Asn Pro Val Tyr Gly Asn Gln Leu
1 5 10 15
Phe Met
<210> 33
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 33
Ser Trp Asn Pro Val Tyr Gly Asn Gln Leu Phe Met Lys Thr Arg Asn
1 5 10 15
Gly Ser
<210> 34
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 34
Gly Asn Gln Leu Phe Met Lys Thr Arg Asn Gly Ser Met Lys Ala Ala
1 5 10 15
Glu Asn
<210> 35
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 35
Lys Thr Arg Asn Gly Ser Met Lys Ala Ala Glu Asn Phe Leu Asp Pro
1 5 10 15
Asn Lys
<210> 36
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 36
Met Lys Ala Ala Glu Asn Phe Leu Asp Pro Asn Lys Ala Ser Ser Leu
1 5 10 15
Leu Ser
<210> 37
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 37
Phe Leu Asp Pro Asn Lys Ala Ser Ser Leu Leu Ser Ser Gly Phe Ser
1 5 10 15
Pro Asp
<210> 38
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 38
Ala Ser Ser Leu Leu Ser Ser Gly Phe Ser Pro Asp Phe Ala Thr Val
1 5 10 15
Ile Thr
<210> 39
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 39
Ser Gly Phe Ser Pro Asp Phe Ala Thr Val Ile Thr Met Asp Arg Lys
1 5 10 15
Ala Thr
<210> 40
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 40
Phe Ala Thr Val Ile Thr Met Asp Arg Lys Ala Thr Lys Gln Gln Thr
1 5 10 15
Asn Ile
<210> 41
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 41
Met Asp Arg Lys Ala Thr Lys Gln Gln Thr Asn Ile Asp Val Ile Tyr
1 5 10 15
Glu Arg
<210> 42
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 42
Lys Gln Gln Thr Asn Ile Asp Val Ile Tyr Glu Arg Val Arg Asp Asp
1 5 10 15
Tyr Gln
<210> 43
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 43
Asp Val Ile Tyr Glu Arg Val Arg Asp Asp Tyr Gln Leu His Trp Thr
1 5 10 15
Ser Thr
<210> 44
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 44
Val Arg Asp Asp Tyr Gln Leu His Trp Thr Ser Thr Asn Trp Lys Gly
1 5 10 15
Thr Asn
<210> 45
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 45
Leu His Trp Thr Ser Thr Asn Trp Lys Gly Thr Asn Thr Lys Asp Lys
1 5 10 15
Trp Thr
<210> 46
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 46
Asn Trp Lys Gly Thr Asn Thr Lys Asp Lys Trp Thr Asp Arg Ser Ser
1 5 10 15
Glu Arg
<210> 47
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 47
Thr Lys Asp Lys Trp Thr Asp Arg Ser Ser Glu Arg Tyr Lys Ile Asp
1 5 10 15
Trp Glu
<210> 48
<211> 18
<212> PRT
<213> 金黄色葡萄球菌(Staphylococcus aureus)
<400> 48
Asp Arg Ser Ser Glu Arg Tyr Lys Ile Asp Trp Glu Lys Glu Glu Met
1 5 10 15
Thr Asn
Claims (13)
1.一种用于诊断或防治金黄色葡萄球菌感染的α溶血素抗原表位肽，其特征在于，包含氨基酸序列为SEQ ID NO:1的多肽，所述抗原表位肽是氨基酸序列为SEQ ID NO:29或SEQID NO:30的多肽。
2.一种用于诊断或防治金黄色葡萄球菌感染的α溶血素抗原表位肽，其特征在于，在权利要求1所述的抗原表位肽的N端或C端偶联多肽标记。
3.如权利要求2所述的α溶血素抗原表位肽，其特征在于，所述多肽标记为生物素标记或荧光标记。
4.一种用于制备抗金黄色葡萄球菌的抗体的融合蛋白，其特征在于，所述融合蛋白由如权利要求1所述的α溶血素抗原表位肽和载体蛋白组成；所述载体蛋白选自匙孔血蓝蛋白（KLH）、牛血清白蛋（BSA）、甲状腺球蛋白、纤维蛋白原、明胶或多聚抗原肽中的一种。
5.如权利要求1-3中任一项所述的α溶血素抗原表位肽在制备用于诊断金黄色葡萄球菌感染的药物中的应用。
6.一种用于金黄色葡萄球菌感染的诊断试剂，其特征在于，还有如权利要求1-3中任一项所述的α溶血素抗原表位肽。
7.如权利要求6所述的诊断试剂，其特征在于，所述α溶血素抗原表位肽包被于检测载体上，所述检测载体选自聚苯乙烯微量反应板、胶体金试剂条、磁珠和微流控芯片中的任一种。
8.如权利要求7所述诊断试剂，其特征在于，还有特异性识别人IgG抗体的第二抗体。
9.如权利要求8所述诊断试剂，其特征在于，所述第二抗体选自兔抗人单克隆抗体、兔抗人多克隆抗体、鼠抗人单克隆抗体、鼠抗人多克隆抗体、羊抗人多克隆抗体或羊抗人多克隆抗体中的一种。
10.如权利要求8所述诊断试剂，其特征在于，所述第二抗体偶联有激活或猝灭特异性荧光基团的配合基团。
11.如权利要求1所述的α溶血素抗原表位肽在制备用于预防和/或治疗金黄色葡萄球菌感染的药物中的应用，所述抗原表位肽是氨基酸序列为SEQ ID NO:30的多肽。
12.一种用于预防或治疗金黄色葡萄球菌感染的药物，其特征在于，包含如权利要求1所述的α溶血素抗原表位肽和药学上可接受的辅料，所述抗原表位肽是氨基酸序列为SEQID NO:30的多肽。
13.如权利要求12所述的药物，其特征在于，还包含药学上可接受的佐剂，所述佐剂为Quil-A佐剂。
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