腸出血性大腸桿菌(EHEC)O157:H7多價(jià)基因工程疫苗的實(shí)驗(yàn)研究
發(fā)布時(shí)間:2018-04-18 06:04
本文選題:腸出血性大腸桿菌(EHEC) + O157:H7; 參考:《第三軍醫(yī)大學(xué)》2005年碩士論文
【摘要】:O157:H7 大腸桿菌是腸出血性大腸桿菌(EHEC)的一個(gè)主要血清型,感染該菌可使人患腹瀉、出血性結(jié)腸炎(hemorrhagic colitis,HC),也可引發(fā)溶血性尿毒綜合征(hemolytic uremic syndrome , HUS) 及血栓形成性血小板減少性紫癜(thrombotic thrombocytopenic purpura,TTP)等嚴(yán)重并發(fā)癥,嚴(yán)重者可導(dǎo)致死亡。EHEC O157 的感染因具有暴發(fā)流行趨勢(shì)、強(qiáng)烈的致病性與致死性和抗生素治療可加劇病情的危險(xiǎn)性等特點(diǎn),已經(jīng)成為全球性的公共衛(wèi)生問(wèn)題。目前EHEC O157:H7 的全基因組測(cè)序已經(jīng)完成,然而目前對(duì)其感染仍缺乏有效的防治方法,研究證明抗菌藥物可促使菌體破壞,釋放志賀毒素增加,從而使并發(fā)HUS 的危險(xiǎn)性增加。因此,尋找有效的針對(duì)性防治方法如疫苗對(duì)防治O157:H7 的感染有著極其重大的意義。人類(lèi)同病原微生物長(zhǎng)期斗爭(zhēng)的歷史表明,疫苗是預(yù)防和抑制傳染病的有力武器。由于O157 的暴發(fā)流行和治療上的困難,疫苗研究就顯得尤其緊迫。 為了評(píng)估疫苗的保護(hù)效果,建立一個(gè)與人類(lèi)病變相似的動(dòng)物模型極為重要。對(duì)于O157 菌,其易感動(dòng)物為牛、羊、豬等大型哺乳動(dòng)物,不適合實(shí)驗(yàn)室應(yīng)用;而小型實(shí)驗(yàn)動(dòng)物如大鼠、小鼠等都不是O157 菌的天然易感動(dòng)物,須降低其對(duì)O157 的抵抗力或增強(qiáng)O157 對(duì)其的致病力,才有可能建立相應(yīng)的動(dòng)物模型。 目前已公認(rèn)的與EHEC 致病性有關(guān)的致病基因主要有eae 基因、stx 基因、溶血素hly 基因還有III 型分泌蛋白EspA、B、D 等。緊密粘附素(Intimin)介導(dǎo)細(xì)菌與腸上皮細(xì)胞的緊密粘附,是O157 最主要的定植因子,尤其是它的約C 端1/3 部分(Intimin-C)為胞外功能區(qū),與相應(yīng)受體結(jié)合,且具有良好的免疫原性和免疫保護(hù)性,是理想的疫苗備選抗原之一。 EHEC O157可以產(chǎn)生兩種志賀毒素,志賀毒素Ⅰ(Stx1)和志賀毒素Ⅱ(Stx2)。其中Stx2為分泌型表達(dá),由1個(gè)A亞單位和5個(gè)B亞單位組成,A亞單位具有細(xì)胞內(nèi)毒性,能與28S rRNA作用從而抑制蛋白質(zhì)合成,是大腸桿菌O157:H7引起臨床表現(xiàn)的病理基礎(chǔ);B亞單位具有細(xì)胞結(jié)合特性,能與具有特定受體(Gb3)的細(xì)胞結(jié)合,從而引導(dǎo)A亞單位發(fā)揮作用。多數(shù)O157:H7細(xì)菌產(chǎn)生Stx2,與溶血性尿毒綜合征(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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