肠出血性大肠杆菌（EHEC）O157：H7多价基因工程疫苗的实验研究

发布时间：2018-04-18 06:04

  本文选题：肠出血性大肠杆菌(EHEC) + O157:H7　； 参考：《第三军医大学》2005年硕士论文

【摘要】：O157:H7 大肠杆菌是肠出血性大肠杆菌(EHEC)的一个主要血清型,感染该菌可使人患腹泻、出血性结肠炎(hemorrhagic colitis,HC),也可引发溶血性尿毒综合征(hemolytic uremic syndrome , HUS) 及血栓形成性血小板减少性紫癜(thrombotic thrombocytopenic purpura,TTP)等严重并发症,严重者可导致死亡。EHEC O157 的感染因具有暴发流行趋势、强烈的致病性与致死性和抗生素治疗可加剧病情的危险性等特点,已经成为全球性的公共卫生问题。目前EHEC O157:H7 的全基因组测序已经完成,然而目前对其感染仍缺乏有效的防治方法,研究证明抗菌药物可促使菌体破坏,释放志贺毒素增加,从而使并发HUS 的危险性增加。因此,寻找有效的针对性防治方法如疫苗对防治O157:H7 的感染有着极其重大的意义。人类同病原微生物长期斗争的历史表明,疫苗是预防和抑制传染病的有力武器。由于O157 的暴发流行和治疗上的困难,疫苗研究就显得尤其紧迫。 为了评估疫苗的保护效果,建立一个与人类病变相似的动物模型极为重要。对于O157 菌,其易感动物为牛、羊、猪等大型哺乳动物,不适合实验室应用;而小型实验动物如大鼠、小鼠等都不是O157 菌的天然易感动物,须降低其对O157 的抵抗力或增强O157 对其的致病力,才有可能建立相应的动物模型。 目前已公认的与EHEC 致病性有关的致病基因主要有eae 基因、stx 基因、溶血素hly 基因还有III 型分泌蛋白EspA、B、D 等。紧密粘附素(Intimin)介导细菌与肠上皮细胞的紧密粘附,是O157 最主要的定植因子,尤其是它的约C 端1/3 部分(Intimin-C)为胞外功能区,与相应受体结合,且具有良好的免疫原性和免疫保护性,是理想的疫苗备选抗原之一。 EHEC O157可以产生两种志贺毒素,志贺毒素Ⅰ(Stx1)和志贺毒素Ⅱ(Stx2)。其中Stx2为分泌型表达,由1个A亚单位和5个B亚单位组成,A亚单位具有细胞内毒性,能与28S rRNA作用从而抑制蛋白质合成,是大肠杆菌O157:H7引起临床表现的病理基础;B亚单位具有细胞结合特性,能与具有特定受体(Gb3)的细胞结合,从而引导A亚单位发挥作用。多数O157:H7细菌产生Stx2,与溶血性尿毒综合征(HUS)及血栓形
[Abstract]:O157:H7 Escherichia coli is a major serotype of enterohemorrhagic Escherichia coli.Hemolytic uremic syndrome (HUSS) and thrombocytopenic purpura (TTP) can also be caused by hemorrhagic colitis. In severe cases, the infection of .EHECO157 may be caused by an outbreak of epidemic trend, which may lead to death in patients with hemorrhagic colitis, such as hemolytic uremic syndrome (HUSS) and thrombocytopenic purpura of thrombocytopenic purpura (thrombocytopenic purpura).The characteristics of strong pathogenicity and mortality, and antibiotic therapy can aggravate the risk of disease, has become a global public health problem.At present, the whole genome sequencing of EHEC O157:H7 has been completed. However, there is still no effective method to prevent and cure the infection of EHEC O157:H7. It has been proved that antimicrobial agents can induce the destruction of bacteria and increase the release of Shiga toxin, thus increasing the risk of concurrent HUS.Therefore, it is of great significance to find effective methods such as vaccine to prevent and cure O157:H7 infection.The long history of human struggle with pathogenic microorganisms shows that vaccine is a powerful weapon to prevent and suppress infectious diseases.Because of the outbreak of O 157 and treatment difficulties, vaccine research is particularly urgent.In order to evaluate the protective effect of the vaccine, it is very important to establish an animal model similar to human disease.For O157, the susceptible animals are large mammals, such as cattle, sheep and pigs, which are not suitable for laboratory use, while small laboratory animals such as rats and mice are not naturally susceptible to O157.It is necessary to reduce its resistance to O157 or to enhance its pathogenicity in order to establish corresponding animal models.At present, the main pathogenicity genes related to the pathogenicity of EHEC are eae gene, hemolysin hly gene and III type secretory protein, EspAgnib D, and so on.Tight adhesion between bacteria and intestinal epithelial cells mediated by close-adhesion hormone (Intimin) is the most important colonization factor of O157, especially its C terminal 1 / 3 part of Intimin-Cis is an extracellular functional region, binds to the corresponding receptor, and has good immunogenicity and immunogenicity.It is one of the ideal vaccine candidate antigens.EHEC O157 can produce two kinds of Shiga toxin, Shiga toxin 鈪，

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