CN113717263A - 一种艰难梭菌特异性抗原肽 - Google Patents
一种艰难梭菌特异性抗原肽 Download PDFInfo
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- CN113717263A CN113717263A CN202110889399.3A CN202110889399A CN113717263A CN 113717263 A CN113717263 A CN 113717263A CN 202110889399 A CN202110889399 A CN 202110889399A CN 113717263 A CN113717263 A CN 113717263A
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- clostridium difficile
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Abstract
本发明涉及一种艰难梭菌特异性抗原肽，特别是针对高产毒艰难梭菌RT027的特异性抗原肽，其包含如SEQ ID No.1所示的氨基酸序列。利用本发明的特异性肽段及其特异性抗体，可以开发新的艰难梭菌高产毒株检测试剂盒和艰难梭菌疫苗，对于艰难梭菌高产毒株感染的检测和治疗具有重要意义。
Description
技术领域
本发明涉及一种艰难梭菌特异性抗原肽。
背景技术
艰难梭菌（Clostridioides difficile，CD）是一种革兰染色阳性，能产生芽孢的专性厌氧菌。CD是医院抗生素相关性腹泻（Antibiotic-associated diarrhea, AAD）的主要病原菌，可以导致轻到重度的腹泻、结肠炎、伪膜性肠炎、中毒性巨结肠等，严重者甚至可导致死亡。近年来，高产毒艰难梭菌（RT027/NAP1/BI/ST01）的出现，导致艰难梭菌感染（Clostridiodes difficile infection, CDI）的发病率和死亡率逐渐增高，每年致全球数万人死亡，治疗费用高达数十亿美元。
2013年，美国CDC（Center for Disease Control and Prevention）将艰难梭菌感染列为“微生物导致公共健康威胁”紧迫级的首位。艰难梭菌致病主要是通过芽孢经粪-口途径进入人体定植在结肠，当长期使用广谱抗生素或质子泵抑制剂等导致肠道菌群失衡后，艰难梭菌大量繁殖产生肠毒素A（TcdA）和细胞毒素B（TcdB），破坏肠道细胞骨架，使得细胞通透性增高，最终导致腹泻等疾病症状。艰难梭菌感染（CDI）的发病机制在很大程度上归因于这两种毒素。针对这些毒素的增强的全身体液免疫反应已被证明对复发性CDI具有保护作用。
多年来，针对这两种毒素的全人类单克隆抗体已经被开发出来，试图对抗不断增加的复发性CDI发病率。也有研究将两种毒素制备疫苗进行接种试验。然而，目前使用毒素A和毒素B制备的疫苗的临床研究显示，虽然有93.3%的志愿者产生2倍以上的毒素A的抗体，有82.2%的志愿者产生2倍以上的毒素B抗体。但是，接种组和对照组的CDI发病率没有显著差异，表明疫苗没有显著疗效。其他一些疫苗试验正在进行中，得出它们的疗效还为时过早。
当前研究认为，除两种艰难梭菌毒素外，其鞭毛、菌毛以及部分表面蛋白也可作为毒力因子在艰难梭菌的定植和致病过程中起着重要作用。例如，细胞壁结合蛋白（cellwall binding proteins，CWPs）Cwp66、Cwp8、Cwp2等是参与定植的重要粘附因子；半胱氨酸蛋白酶Cwp84参与表面蛋白和纤维蛋白的切割；鞭毛相关蛋白还会影响毒力的表达。有研究表明，去除某些表面蛋白或用相应抗体处理艰难梭菌可减少艰难梭菌的定植。艰难梭菌表面S层（SlpA）的抗体可消除艰难梭菌对小鼠929和人HeLa细胞的粘附。细胞壁蛋白Cwp84作为疫苗进行仓鼠免疫后，与未经免疫的对照组相比，用Cwp84免疫过的仓鼠感染模型中，艰难梭菌在肠道的定植减少，总体生存率也有所提高。但是，目前这些表面相关蛋白的免疫试验结果表明，这些蛋白仍不能达到有效清除艰难梭菌的效果，急需寻找更多的用于艰难梭菌疫苗制备的免疫原性靶蛋白，以期制备特异有效的艰难梭菌疫苗。
发明内容
本发明的目的是提供一种新的具有免疫源性的艰难梭菌特异性抗原肽。
本发明采用如下技术方案：
一种艰难梭菌特异性抗原肽，特别是针对高产毒艰难梭菌RT027的特异性抗原肽，其包含如SEQ ID No.1所示的氨基酸序列。
一种编码如上述艰难梭菌特异性抗原肽的核酸分子，其包含如SEQ ID No.2所示的核苷酸序列。
一种包含如上述核酸分子的载体。
一种利用如上述艰难梭菌特异性抗原肽制备的抗体。
一种利用如上述艰难梭菌特异性抗原肽制备的疫苗，所述疫苗用于刺激宿主生物的免疫应答反应。
一种艰难梭菌特异性抗原蛋白，其为包含如SEQ ID No.1所示的氨基酸序列的膜蛋白。
进一步的，所述艰难梭菌特异性抗原蛋白包含如SEQ ID No.3所示的氨基酸序列。
本发明的有益效果在于：利用本发明的特异性肽段及其特异性抗体，可以开发新的艰难梭菌高产毒株检测试剂盒和艰难梭菌疫苗，对于艰难梭菌高产毒株感染的检测和治疗具有重要意义。
附图说明
图1为RT027与RT017型艰难梭菌膜蛋白差异蛋白条带。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其它实施例，都属于本发明保护的范围。
1、艰难梭菌的培养
本发明选取4株高产毒艰难梭菌RT027型菌株（RT027/NAP1/BI/ST01）和3株低产毒艰难梭菌RT017型菌株，进行细菌培养。菌株使用前将冷冻保藏的菌株室温融化，接种于CDMN选择性培养基，三区划线后置于厌氧罐内37℃培养48~72h。挑选单个菌落转种CDMN培养培养基分离纯化待用。
2、提取艰难梭菌膜蛋白
对于制备膜蛋白的菌株，使用无菌0.1 mol/L PBS洗涤新鲜培养的艰难梭菌细胞3次。配制浓度为250 μg/ml的EZ-Link Sulfo-NHS-SS-biotin生物素反应液，标记新鲜洗涤的细菌细胞膜蛋白。将标记的菌体细胞超声破碎（3s on/7s off，强度20%，5 min）。4 ℃条件下，12,000 g离心30 min，收集富含艰难梭菌膜蛋白的上清液。而后，使用亲和素蛋白层析柱纯化膜蛋白。
3、将提取到的膜蛋白进行聚丙烯酰胺凝胶电泳，经考马斯亮蓝染色后得到每株菌相应的条带图谱，将两种菌株的差异凝胶条带进行胶内酶解和质谱分析（见图1）。
4、分析差异条带中蛋白种类和肽段差异
将高产毒株RT027和低产毒株RT017型在15KD水平的差异凝胶条带全部进行质谱鉴定后，共得225种蛋白。去重后在RT027组中有9种特异蛋白，包含转运类蛋白（CDIF1296T_02941等），代谢类蛋白（atpF等），粘附蛋白（fliL，pilin）以及其他膜蛋白。去重后在RT017组中有3种特异蛋白，包括转运类蛋白（IM33_15590）等。基于特征肽段的一级质谱信号（峰面积）进行定量分析，结果发现菌毛蛋白（pilin）的肽段（SEQ ID No.1：SASLSYYADESK）特性异性的存在于RT027菌株，为特异性的差异肽段。该差异肽段对应的核苷酸序列为SEQ IDNo.2：GCAGATGATTTTACTGCTGATAATTTAAAG。
该肽段所属的蛋白为菌毛蛋白（pilin protein：C9YNN2）。序列为SEQ ID No.3：MKNKKGFTLVELLVVIAIIGILAIIALPALFKNIEKAKIAKLEADISAIKSASLSYYADESKYTDGGMISWVKKDGKIIINGGFKDDPLADKIENLGMPYNGSYLLMSSPGHEKYLELSILPEGEISKSGLDKLKNDYGNLIDITNDQNKINIVIKLLNNKSNT
5、按照鉴定序列合成差异肽段
精密称量氨基酸A-0.527g\D-0.696g\E-0.72g\L-0.598g\K-0.793g\ S-0.649g\Y-0.778g 分别以4ml DMF过夜溶解。精密量取DIEA 56ml以DMF稀释至200ml。精密称量HBTU-32.1g HOBT-11.4g，混合后以DMF溶解定容至200ml。精密量取哌啶60ml以DMF定容至200ml。精密称量氨基树脂0.05g。待试剂与氨基酸完全溶解后开始合成。
重复以下步骤依次加入相应氨基酸进行肽段合成：溶胀氨基树脂；脱FOMC；洗脱；加入氨基酸；加入HBTU与HOBT混合溶剂；加入DIEA；洗脱。肽链合成完毕后以DCM再次洗脱，而后进行多肽裂解，再用冰乙醚进行洗脱，对沉淀物进行冻干得到相应的肽段。
6、制备抗体
采购Balb/c小鼠，适应性饲养一周。称重，挑选体重相近5只小鼠。将合成的冻干肽段样本用纯水溶解，将载体蛋白KLH（10mg/L）与多肽（4mg/ml）按体积2∶1进行混匀后进行免疫。混匀完全的多肽溶液用PBS（pH 7.4）透析最少3次，每次间隔不少与3小时。最后用过滤后的PBS定容至3.3ml，分装3管，每管1.1ml，-20摄氏度储存。多肽免疫浓度为100ug/只。
免疫小鼠时取1管，放置恢复室温后与弗氏完全佐剂比例混匀（多肽溶液∶完全佐剂=1∶1.5），乳化完全后，左手抓起小鼠背部皮肤，消毒腹部，头低位固定，右手持注射器进行腹腔注射（落空感，回抽无液），每只小鼠注射0.5ml，进行第一次免疫。第二次，三次免疫的时候用弗氏不完全佐剂1∶1.5比例混匀。共免疫三次，第1免疫与第2次免疫间隔2周，第2次免疫和第3次免疫间隔2周。第3次免疫后7-10天后，摘眼球取血，3500-4000转离心，取上清，采用ElISA方法检测效价。发现免疫发现后可以得到效价大于1∶1000的抗体。证实该肽段确实有免疫原性。
SEQUENCE LISTING
<110> 河北医科大学第二医院
<120> 一种艰难梭菌特异性抗原肽
<130> 2021
<160> 3
<170> PatentIn version 3.3
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<213> 人工合成
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<213> 人工合成
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gcagatgatt ttactgctga taatttaaag 30
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Claims (7)
1.一种艰难梭菌特异性抗原肽，其特征在于，其包含如SEQ ID No.1所示的氨基酸序列。
2.一种编码如权利要求1所述的艰难梭菌特异性抗原肽的核酸分子，其特征在于，其包含如SEQ ID No.2所示的核苷酸序列。
3.一种包含如权利要求2所述的核酸分子的载体。
4.一种利用如权利要求1所述的艰难梭菌特异性抗原肽制备的抗体。
5.一种利用如权利要求1所述的艰难梭菌特异性抗原肽制备的疫苗，所述疫苗用于刺激宿主生物的免疫应答反应。
6.一种艰难梭菌特异性抗原蛋白，其特征在于，其为包含如SEQ ID No.1所示的氨基酸序列的膜蛋白。
7.根据权利要求6所述的艰难梭菌特异性抗原蛋白，其特征在于，其包含如SEQ IDNo.3所示的氨基酸序列。
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| WO2010135585A2 (en) * | 2009-05-20 | 2010-11-25 | University Of Maryland, Baltimore | Engineered type iv pilin of clostridium difficile |
| CN103237807A (zh) * | 2010-10-05 | 2013-08-07 | 卫生防护机构 | 艰难梭菌抗原 |
| WO2013150309A1 (en) * | 2012-04-04 | 2013-10-10 | The Secretary Of State For Health | Clostridium difficile antigens |
| WO2019012406A1 (en) * | 2017-07-11 | 2019-01-17 | National Research Council Of Canada | SPECIFIC ANTIBODIES AGAINST CLOSTRIDIUM DIFFICILE AND THEIR APPLICATIONS |
| WO2020115648A1 (en) * | 2018-12-04 | 2020-06-11 | Instytut Immunologii I Terapii Doświadczalnej Im. Ludwika Hirszfelda Polskiej Akademii Nauk | Vaccine for the prevention and treatment of c. difficile infections and the use thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023011267A1 (zh) * | 2021-08-04 | 2023-02-09 | 河北医科大学第二医院 | 一种艰难梭菌特异性抗原肽 |
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| WO2023011267A1 (zh) | 2023-02-09 |
| CN113717263B (zh) | 2022-06-07 |
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