StcE, an E.coli O157:H7 Protease Specific for C1-Inh

肠出血性大肠杆菌（EHEC），主要是血清型O 157：H7，估计引起20000例 美国每年的疟疾病例。2-6感染者的百分比，大多数是年轻人 儿童发展为严重的肾脏疾病，即溶血性尿毒综合征（HUS）。肠出血性大肠杆菌致病性 导致出血性结肠炎和HUS的因素知之甚少，但对某些机制的了解已经 最近出现的。内膜介导的粘附和III型效应物由染色体位点编码 叫李。由噬菌体编码的滋贺毒素（Stx）是引起EHEC的重要因素 疾病肠出血性大肠杆菌菌株通常具有大质粒，原型为pO 157。我们已经确定 一个新的pO 157基因stcE，它编码一种细胞外锌金属内切蛋白酶（ZMP）， 切割关键的抗炎调节剂Cl-酯酶抑制剂（Cl-Inh）。C1-Inh是丝氨酸蛋白酶 抑制剂（seq）in），其提供对参与经典和 甘露聚糖结合配体补体激活、接触激活和内源性凝血。Cl-Inh抑制 多种蛋白酶：Clr和Cls、MASP-1、MASP-2、激肽释放酶、FXIIa、FXIa和纤溶酶。缺陷 Cl-Inh引起严重的临床综合征。最著名的是遗传性血管性水肿（HAE），一种遗传性血管性水肿。 Cl-Inh缺乏，其特征在于肠痉挛，呕吐， 腹泻和危及生命的气管肿胀。标记的StcE与培养的 巨噬细胞、B细胞和T细胞。因此，StcE是一个不断增长的ZMP类别的例子，如破伤风， 肉毒杆菌和炭疽致命因子毒素。这些ZMP，与同源假单胞菌和 弧菌ZMP具有特异性的非细胞外基质蛋白靶点。我们将检验StcE 降解可溶性或细胞相关的Cl-Inh，这导致丝氨酸蛋白酶级联调节不良 包括补体激活、接触激活和凝血。这种失调 导致局部炎症、组织损伤和水肿。StcE结构的解析和 这些功能可能为EHEC的化学治疗或免疫预防或治疗提供新的靶点 感染，现在最好的管理只有支持性治疗。

Enterohemorrhagic Escherichia coli (EHEC), principally serotype O157:H7, cause an estimated 20,000 cases of diarrheal disease in the United States per year. 2-6 % of the infected individuals, mostly young children progress to a severe renal disease, hemolytic uremic syndrome (HUS). The EHEC pathogenic factors that lead to bloody colitis and HUS are poorly understood, but knowledge of some mechanisms has recently emerged. Intimin-mediated adherence and type III effectors are encoded by a chromosomal locus termed LEE. The phage-encoded Shiga toxins (Stxs) are responsible for significant aspects of EHEC disease. EHEC strains commonly possess large plasmids, the prototype being pO157. We have identified a new pO 157 gene, stcE, which encodes an extraceliular zinc-metalloendoprotease (ZMP) that specifically cleaves the critical anti-inflammatory regulator C l-esterase inhibitor (C 1-Inh). C 1-Inh is a serine protease inhibitor (seq)in) that provides the principal inhibition of the proteolytic cascades involved in classic and mannan-binding ligand complement activation, contact activation and intrinsic coagulation. C l-Inh inhibits diverse proteases: Clr and Cls, MASP-1, MASP-2, kallikrein, FXIIa, FXIa, and plasmin. Deficiencies in Cl-Inh cause profound clinical syndromes. The best known is hereditary angioedema (HAE), a genetic deficiency in Cl-Inh, which is characterized by transient, recurrent attacks of intestinal cramps, vomiting, diarrhea and life-threatening episodes of tracheal swelling. Fluorescenated StcE binds to cultured macrophages, B- and T-cells. Thus, StcE is an example of a growing class of ZMPs such as tetanus, botulinum and anthrax lethal factor toxins. These ZMPs, in contrast to the homologous Pseudomonas and Vibrio ZMPs, have specific, non-extracellular matrix protein targets. We will test the hypothesis that StcE degrades soluble or cell-associated Cl-Inh, and this results in poorly regulated serine protease cascades involving complement activation, contact activation and coagulation. This dysregulation would then contribute to local inflammation, tissue damage and edema. The elucidation of StcE structure and function(s) may result in new targets for chemotherapeutic or immune prevention or treatment of EHEC infections, which now are best managed only by supportive therapy.