幽门螺杆菌CagA羧基端多态性分析及诱导AGS IL-8表达水平研究
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摘要
幽门螺杆菌(Helicobacter pylori,简称H.pylori或HP)感染是慢性胃炎、消化性溃疡、胃癌的主要致病因素,严重胃部疾病患者携带的HP通常含cag致病岛(cag PAI),其中所包含的cagA基因编码的细胞毒素相关蛋白A(CagA)介导宿主胞内一系列信号转导反应最终致不同程度的炎性组织损伤甚至癌变。西方国家患者感染cagA~+HP患严重胃肠道疾病几率明显增高,而东亚国家患者cagA~+检出率达90%以上,不同东亚菌株间CagA羧基端多态性与不同临床结局密切相关。CagA磷酸化位点位于羧基端EPIYA基序(Glu-Pro-Ⅱe-Tyr-Ala)的酪氨酸残基,EPIYA多态性在东西方HP中主要表现在其侧翼保守序列、EPIYA基序本身及其拷贝数上。目前根据EPIYA侧翼保守序列特征可将HP分为西方型和东亚型:东亚型HP CagA具有高亲和SHP-2 SH2结构域的序列(SHP-2 bindingsequence,ESS),可有效激活胞内磷酸化激酶级联系统,与西方型HP相应序列存在明显差异,西方型HP EPIYA-C基序与上述共有序列匹配程度较低,致病力相对较弱。上述东西方HP CagA羧基端序列特征决定了东亚型HP CagA在功能上不同于西方型HP携带的CagA。由于HP的高度重组及变异特征,经典HP东西方分型理论依赖的保守区出现局部或整体缺失、突变,这对现有CagA序列特征与HP致病力的认识提出了挑战。同时,EPIYA-A和B通过抑制性磷酸化基序对上述环路起负反馈调节,近年有研究认为完整的EPIYA-B基序对HP感染引起宿主细胞前炎性因子IL-8高水平分泌十分关键。可见,HP CagA羧基端多态性与致病力关系复杂,尤其在东亚型HP普遍具有CagA蛋白的情况下,引起临床疾病严重程度差异较大,HP CagA羧基端序列特征、对宿主的致病力机制研究对HP感染的防治具有重要意义。
本实验选用100株中国浙江HP临床菌株进行CagA羧基端序列扩增,与NCBI核苷酸/氨基酸数据库中世界各地来源的287株该序列区信息一同进行氨基酸水平比对分析,发现东西方HP又一保守的差异特征标志,该段序列长度在6-19个氨基酸残基,位于CagA第840氨基酸残基附近,侧翼序列保守性高,利用该标志序列可将HP东西方分型效力从经典方法的80.10%提高至98.45%,两种方法一致率99.44%,因而该标志点有助于今后在氨基酸序列特征上分析东西方HP致病机制的不同。
本实验发现一株携带EPIYA-A-D的中国浙江HP菌株,经100:1感染比体外攻击AGS细胞4小时及36小时均导致宿主细胞IL-8表达水平均较携带1～2个EPIYA-B的浙江菌株及西方型HP26695高,提示中国HP促进宿主细胞高水平表达IL-8不依赖EPIYA-B,不同于西方菌株相应致炎机制,与HP EPIYA-B具有胞内信号转导负反馈调控作用结论一致。此外,HP感染宿主细胞机制中介导CagA多聚化的CM序列特征在东西方HP中明显不同,再次提示东西方HP CagA作为毒力因子致病机制的差异及复杂性。
Helicobacter pylori(H.pylori) is the main pathogenic factor of chronic gastritis, peptic ulcer and gastric cancer.Patients with serious gastric diseases are usually infected by H.pylori containing cag PAI,Cytotoxin-associated protein A(CagA) coded by cagA participates in a series of signal transductions in host cells and results in inflammatory damage of tissues even canceration on different levels.Patients in the western who suffer from serious gastric disorders are infected by cagA~+ H.pylori, while 90%patients in East Asian are infected by cagA~+ HP,the polymorphism of CagA carboxy-terminal sequence among various strains in East Asian leads to diverse clinical endings.The phosphorylation site of CagA exists in the Tyr locating in EPIYA (Glu-Pro-Ⅱe-Tyr-Ala) motif,and mainly shows in surrounding sequences and the repetition of EPIYA.Based on the surrounding sequences of EPIYA,H.pylori,all over the world,are divided into Western and East Asian types.The East Asian-type CagA binds to SHP-2 more strongly than the Western-type because of the East Asian SHP-2-binding sequence(ESS),which activates effectively the phosphorylation kinase system in cells.The Western-type CagA contains WSS and shows weak pathogenicity.These facts indicate the function of CagA is different between H.pylori strains in East Asian and Western.Due to largely recombination and variation of H. pylori,conservative regions used by classical typing theory appear deletion and mutation in some cases partially or integrally,which make a challenge to current recognitions about structural characteristics of CagA and the correlative pathogenicity. EPIYA-A and B motifs act inverse feedback to the phosphorylation through suppressant phosphorylated motifs.Certain investigation indicated that the completed EPIYA-B is essential during the expression of pro-inflammator IL-8 in infected host cells.Therefore,the relationship between the polymorphism of H.pylori CagA Cterminal characters and pathogenicity is intricate,expecially among East Asian strains which almost all carry with the CagA.
100 C-sequences of H.pylori CagA amplified from Zhejiang strains and other 287 strains submitted in NCBI from all over the world participated in the study,and were implemented the multiple sequence alignment.The result indicated a new potential oligopeptide biomarker which contained 6 to 19 residues,located around the 840~(th) amino acid residue of CagA and possessed highly conservative surrounding sequences could enhance the validity of H.pylori identification from 80.10%used by classical method to 98.45%,the consistency of two methods reached to 99.44%,and it may be as a characteristic marker in further study of cagA~+ H.pylori pathogenicity.
Furthermore,a Chinese H.pylori isolate carrying EPIYA-A-D,which naturally EPIYA-B absence but showed stronger activity in stimulation of IL-8 expression compared to other Chinese strains and Western 26695,both after co-culture with AGS 4h and 36h.This suggested the IL-8 expression in host cells was independent of EPIYA-B in Chinese H.pylori,which was significantly different from Western strains' correlative mechanism.The Alignment results also indicated CagA multimerization(CM) sequence appeared different characteristics between Western and East Asian H.pylori.
本实验选用100株中国浙江HP临床菌株进行CagA羧基端序列扩增,与NCBI核苷酸/氨基酸数据库中世界各地来源的287株该序列区信息一同进行氨基酸水平比对分析,发现东西方HP又一保守的差异特征标志,该段序列长度在6-19个氨基酸残基,位于CagA第840氨基酸残基附近,侧翼序列保守性高,利用该标志序列可将HP东西方分型效力从经典方法的80.10%提高至98.45%,两种方法一致率99.44%,因而该标志点有助于今后在氨基酸序列特征上分析东西方HP致病机制的不同。
本实验发现一株携带EPIYA-A-D的中国浙江HP菌株,经100:1感染比体外攻击AGS细胞4小时及36小时均导致宿主细胞IL-8表达水平均较携带1～2个EPIYA-B的浙江菌株及西方型HP26695高,提示中国HP促进宿主细胞高水平表达IL-8不依赖EPIYA-B,不同于西方菌株相应致炎机制,与HP EPIYA-B具有胞内信号转导负反馈调控作用结论一致。此外,HP感染宿主细胞机制中介导CagA多聚化的CM序列特征在东西方HP中明显不同,再次提示东西方HP CagA作为毒力因子致病机制的差异及复杂性。
Helicobacter pylori(H.pylori) is the main pathogenic factor of chronic gastritis, peptic ulcer and gastric cancer.Patients with serious gastric diseases are usually infected by H.pylori containing cag PAI,Cytotoxin-associated protein A(CagA) coded by cagA participates in a series of signal transductions in host cells and results in inflammatory damage of tissues even canceration on different levels.Patients in the western who suffer from serious gastric disorders are infected by cagA~+ H.pylori, while 90%patients in East Asian are infected by cagA~+ HP,the polymorphism of CagA carboxy-terminal sequence among various strains in East Asian leads to diverse clinical endings.The phosphorylation site of CagA exists in the Tyr locating in EPIYA (Glu-Pro-Ⅱe-Tyr-Ala) motif,and mainly shows in surrounding sequences and the repetition of EPIYA.Based on the surrounding sequences of EPIYA,H.pylori,all over the world,are divided into Western and East Asian types.The East Asian-type CagA binds to SHP-2 more strongly than the Western-type because of the East Asian SHP-2-binding sequence(ESS),which activates effectively the phosphorylation kinase system in cells.The Western-type CagA contains WSS and shows weak pathogenicity.These facts indicate the function of CagA is different between H.pylori strains in East Asian and Western.Due to largely recombination and variation of H. pylori,conservative regions used by classical typing theory appear deletion and mutation in some cases partially or integrally,which make a challenge to current recognitions about structural characteristics of CagA and the correlative pathogenicity. EPIYA-A and B motifs act inverse feedback to the phosphorylation through suppressant phosphorylated motifs.Certain investigation indicated that the completed EPIYA-B is essential during the expression of pro-inflammator IL-8 in infected host cells.Therefore,the relationship between the polymorphism of H.pylori CagA Cterminal characters and pathogenicity is intricate,expecially among East Asian strains which almost all carry with the CagA.
100 C-sequences of H.pylori CagA amplified from Zhejiang strains and other 287 strains submitted in NCBI from all over the world participated in the study,and were implemented the multiple sequence alignment.The result indicated a new potential oligopeptide biomarker which contained 6 to 19 residues,located around the 840~(th) amino acid residue of CagA and possessed highly conservative surrounding sequences could enhance the validity of H.pylori identification from 80.10%used by classical method to 98.45%,the consistency of two methods reached to 99.44%,and it may be as a characteristic marker in further study of cagA~+ H.pylori pathogenicity.
Furthermore,a Chinese H.pylori isolate carrying EPIYA-A-D,which naturally EPIYA-B absence but showed stronger activity in stimulation of IL-8 expression compared to other Chinese strains and Western 26695,both after co-culture with AGS 4h and 36h.This suggested the IL-8 expression in host cells was independent of EPIYA-B in Chinese H.pylori,which was significantly different from Western strains' correlative mechanism.The Alignment results also indicated CagA multimerization(CM) sequence appeared different characteristics between Western and East Asian H.pylori.
引文
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