摘要
肠出血性大肠杆菌(EHEC) O157:H7是一种重要的新发人畜共患传染病病原菌。自1975年被首次分离、1982年被确认为致病菌以来的近30年中,世界各地包括中国都有不同规模的暴发流行。EHEC O157:H7感染可使人患腹泻、出血性结肠炎(hemorrhagic colitis , HC) ,还可在5~10%的病例中引发溶血性尿毒综合症(hemolytic uremic syndrome,HUS)及血栓性血小板减少紫癜(thrombotic thrombocytopenic purpura,TTP)等严重并发症,严重者可导致死亡。EHEC O157:H7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。我国已将肠出血性大肠杆菌列为21世纪可能对国人卫生健康有重大影响的12种病原微生物之一。同时,O157:H7菌培养容易、繁殖迅速、感染力强、感染途径广泛,使之极有可能作为未来军事斗争中的细菌战剂和生物恐怖战剂。美国疾病预防控制中心(CDC)已将EHEC O157:H7菌列为B类生物恐怖病原体严加防范。
目前,EHEC O157:H7的全基因组测序已经完成,但对其感染仍缺乏有效的治疗方法。临床上针对O157:H7菌的感染主要采用抗生素治疗及相应的对症治疗。新近的研究发现,抗生素使菌体破裂,导致O157:H7菌志贺样毒素(Shiga like toxin,Stx)的释放水平大大提高,使得抗生素对病程无明显影响甚至导致病程的延长,从而增加发生并发症的危险并引起死亡。人类同感染性疾病作斗争的历史证明,抗体是治疗某些感染性疾病的首选方法。由于O157:H7菌的感染易引起暴发流行,且对其感染尚缺乏有效的治疗方法,治疗性抗体的研究就显得尤为紧迫。
EHEC O157:H7主要产生两种毒素,分别称为志贺样毒素Ⅰ(Stx1)和志贺样毒素Ⅱ(Stx2)。在细菌体内,Stx2为分泌型表达,Stx1为胞内表达。两种毒素均由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,能与具有特定糖鞘脂受体(Gb3)的细胞结合,从而引导A亚单位发挥作用,是志贺样毒素致病的关键。多数O157:H7细菌产生Stx2,而且Stx2毒性强于Stx1,与HUS及TTP等严重并发症的相关性更为密切。因此Stx2是该菌致病性的重要物质基础,是理想的制备
Enterohemorrhagic Escherichia coli (EHEC) O157:H7, an emerging pathogen, causes severe hemorrhagic colitis and the life-threatening extraintestinal complication of hemolytic uremic syndrome (HUS) in 5 to 10% of patients. EHEC O157:H7, produce Shiga like toxin 1 or 2 (Stx1 or Stx2, respectively), or both. The source of EHEC O157:H7 is mainly of contaminated food or drinking water. Treatment of infection with EHEC O157:H7 has been difficult because antibiotics do not change the course of the enteritis of EHEC O157:H7 and may increase the incidence of HUS caused by the pathogen. This untoward effect has been proposed to be mediated by antibiotic-induced bacteriolysis and release of intracellular Shiga like toxins.
Stxs consist of an A-subunit monomer and a B-subunit pentamer. The A subunit’s N-glycosidase activity is activated, resulting in the removal of the adenine group from position 4324 in the eukaryotic 28S rRNA of the 60S ribosomal subunit. The resulting A subunit-mediated inhibition of protein biosynthesisis cytotoxic to the target cell. The B subunit is involved in binding to target cells via its glycolipid receptor, globotriaosylceramide (Gb3-Cer). Stxs can be broadly divided into two groups, Stx1 and Stx2. Stx1 and Stx2 fail to cross neutralize and show differences in biological activities in vitro and in vivo. Since Stx2, but not Stx1, is thought to be a major cause of toxity that induces HUS in humans based on epidemiological analyses and studies on EHEC-infected animals.
Currently there is no effective treatment or prophylaxis for HUS. As in many toxin-mediated diseases, such as tetanus and botulism, little endogenous serum antibody against Stx is induced following EHEC infection. Nonetheless, passively immune therapy with Stx2-neutralizing antibodies should be very useful in preventing the development of HUS in EHEC infections.Thus a specific therapeutic approach is needed for the prevention of severe disease caused by EHEC infections.
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