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

肠出血性大肠杆菌(EHEC)，主要是O157：H7血清型，估计导致20,000人死亡 美国每年的腹泻病病例。2-6%的感染者，主要是年轻人 儿童发展为一种严重的肾脏疾病，溶血性尿毒症综合征(HUS)。肠出血性肠出血性大肠杆菌 导致血性结肠炎和HUS的因素知之甚少，但对一些机制的了解已经 最近才出现的。内膜蛋白介导的黏附和III型效应器由染色体基因座编码 名为李。噬菌体编码志贺毒素(STX)是EHEC的重要致病因子 疾病。EHEC菌株通常具有大的质粒，原型是pO157。我们已经确定了 一个新的Po 157基因，stcE，它编码一种细胞外锌金属内切酶(ZMP)，它特异性地 裂解关键的抗炎调节剂C L-酯酶抑制剂(C1-INH)。C_1-InH是一种丝氨酸蛋白酶 抑制物(Seq)in)，它主要抑制经典和 甘露聚糖结合配体补体激活、接触激活和内凝血。C L-inh抑制作用 不同的蛋白水解酶：CLR和CLS、MASP-1、MASP-2、激肽释放酶、FXIIa、FXIa和纤溶酶。的不足之处 CL-InH可引起严重的临床症状。最广为人知的是遗传性血管性水肿(HAE)，一种遗传性 氯-异烟肼缺乏，其特征是一过性，反复发作的肠道痉挛，呕吐， 腹泻和危及生命的气管肿胀发作。荧光化StcE与培养物结合 巨噬细胞、B细胞和T细胞。因此，STcE是破伤风等日益增长的ZMP的一个例子， 肉毒杆菌和炭疽致命因子毒素。这些ZMP与同源的假单胞菌和 弧菌ZMP具有特定的、非细胞外基质蛋白靶标。我们将检验StcE的假设 降解可溶的或与细胞相关的氯-InH，这导致调节不良的丝氨酸蛋白酶级联 包括补体激活、接触激活和凝血。这种失调将会导致 会导致局部炎症、组织损伤和浮肿。STcE的结构和结构的阐明 S的作用可能为EHEC的化疗或免疫预防或治疗带来新的靶点 感染，现在只有通过支持性治疗才能最好地控制感染。

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.