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

StcE，一种针对 C1-Inh 的大肠杆菌 O157:H7 蛋白酶

• 批准号: 6830289
• 负责人: Rodney A. Welch
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-16 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6830289
• 关键词: StcE; E.coli; O157; H7; Protease

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。肠出血性大肠杆菌（EHEC），主要是血清型O 157：H7，在美国每年估计引起20，000例腹泻病。2-6%的受感染者，大多数是幼儿，进展为严重的肾脏疾病，即溶血性尿毒综合征（HUS）。导致出血性结肠炎和溶血性尿毒综合征的肠出血性大肠杆菌致病因素知之甚少，但最近出现了一些机制的知识。内膜介导的粘附和III型效应子由称为LEE的染色体位点编码。噬菌体编码的滋贺毒素（Stx）是引起EHEC疾病的重要因素。肠出血性大肠杆菌菌株通常具有大质粒，原型为pO 157。我们已经鉴定出一种新的pO 157基因stcE，它编码一种细胞外锌金属内切蛋白酶（ZMP），该蛋白酶特异性切割关键的抗炎调节剂C1-酯酶抑制剂（C1-Inh）。C1-Inh是一种丝氨酸蛋白酶抑制剂（seq），主要抑制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的蛋白水解级联反应。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。Cl-Inh的缺陷导致严重的临床综合征。最著名的是遗传性血管性水肿（HAE），这是一种Cl-Inh的遗传缺陷，其特征在于肠痉挛、呕吐、腹泻和危及生命的气管肿胀发作的短暂反复发作。浓缩的StcE与培养的巨噬细胞、B细胞和T细胞结合。因此，StcE是不断增长的一类ZMP如破伤风、肉毒杆菌和炭疽致死因子毒素的实例。与同源假单胞菌和弧菌ZMP相反，这些ZMP具有特异性的非细胞外基质蛋白靶标。我们将测试StcE降解可溶性或细胞相关的Cl-Inh的假设，这导致调节不良的丝氨酸蛋白酶级联，涉及补体激活，接触激活和凝血。这种失调会导致局部炎症、组织损伤和水肿。StcE结构和功能的阐明可能会导致EHEC感染的化学治疗或免疫预防或治疗的新靶点，目前最好的管理方法是支持性治疗。性能现场=