INTERVENTIONAL STRATEGIES FOR HEMORRHAGIC COLITIS

出血性结肠炎的干预策略

• 批准号: 6177538
• 负责人: EDGAR C. BOEDEKER
• 金额: $ 15.34万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6177538
• 关键词: Escherichia coli infections; active immunization; antiinfective agents; cell adhesion; colitis; cytokine receptors; disease /disorder model; enterotoxins; gastrointestinal disorder chemotherapy; gastrointestinal hemorrhage; hemolytic anemia; hemorrhage; host organism interaction; immunogenetics; immunotherapy; laboratory rabbit; nonhuman therapy evaluation; passive immunization; vascular endothelium permeability

The broad aim of this proposal is to use a new animal model of enterohemorrhagic E.coli (EHEC) infection to understand the molecular pathogenesis of EHEC infection and develop practical interventional strategies to prevent and treat EHEC disease. It is now well recognized that some toxin-producing strains of E.coli, most commonly of serotype O157:H7, induce hemorrhagic colitis which may progress to fatal hemolytic-uremic syndrome. EHEC strains produce potent toxins which are referred to as Shiga-like toxins (SLTs) because of their relatedness to shiga toxin of shigella dysenteriae. Most EHEC share the ability to adhere intimately to intestinal epithelial cells by ~attaching and effacing~ (A/E) mechanisms. Although EHEC attachment mechanisms, with loss of microvilli, may contribute directly to diarrhea; the most severe intestinal and renal manifestations result from toxin-mediated damage to vascular endothelium with tissue edema, inflammatory infiltrates, cytokine production and vascular thrombi. A/E adherence may have profound influence on the delivery of toxin to the host, but this has not been adequately studied. At present, there is no effective prophylaxis or accepted treatment for EHEC disease. The specific aims of the proposal are to use an animal model of EHEC infection to: 1. Examine the influence of A/E adherence on SLT toxicity using mutants in the locus of enterocyte effacement (LEE). 2. Test the ability of passively administered immunoglobulin with anti- toxic activity to prevent EHEC disease. 3. Test the ability of intraluminal toxin-receptor analogs to prevent EHEC disease. 4. Determine whether antibiotic therapy has beneficial or harmful effects on the course of disease. 5. Examine the mediators of inflammation and determine whether anti- inflammatory strategies, in particular recombinant IL-1 receptor antagonist (IL-1ra), and recombinant TNF binding protein (TNF-BP) can alter the disease. 6. Examine strategies for active immunization against EHEC using the toxins, and products of the genes in the locus of enterocyte effacement (LEE). E.coli strain RDEC-H19A infection of rabbits will serve as the animal model of EHEC disease for these studies. RDEC-H19A, produced by the Transfer of the toxin-converting phage H19A of an O26:H11 EHEC to the rabbit entero-pathogenic E.coli RDEC-1, is an attaching and effacing rabbit pathogen. This strain produces high levels of Shiga-like toxin I (SLT-I), colonizes cecum and colon, and induces intestinal disease in rabbits with pathologic changes resembling human EHEC disease. Interventions will limit the interaction of SLTs with endothelium by neutralizing toxin within the vascular compartment; binging toxin in the gut lumen; eliminating the toxin-producing organisms; or inhibiting the action of pro-inflammatory cytokines.

该提案的主要目标是使用一种新的动物模型 了解肠出血性大肠杆菌 (EHEC) 感染的分子机制 EHEC感染的发病机制并制定实用的干预措施 预防和治疗肠出血性大肠杆菌疾病的策略。 现在已被广泛认可 一些产生毒素的大肠杆菌菌株，最常见的是血清型 O157:H7，诱发出血性结肠炎，可能发展至致命 溶血尿毒症综合征。 EHEC 菌株产生强效毒素， 由于与志贺毒素相关，因此被称为志贺样毒素 (SLT) 志贺氏志贺氏菌毒素。 大多数肠出血性大肠杆菌都有以下能力： 通过〜附着和紧密粘附到肠上皮细胞 消除~（A/E）机制。 尽管 EHEC 附着机制， 微绒毛丧失，可能直接导致腹泻；最严重的 肠道和肾脏的表现是由毒素介导的损伤引起的 血管内皮组织水肿、炎症浸润， 细胞因子的产生和血管血栓。 A/E 依从性可能有 对毒素向宿主的输送产生深远的影响，但这 没有得到充分的研究。 目前还没有有效的办法 EHEC 疾病的预防或接受的治疗。 该提案的具体目标是使用肠出血性大肠杆菌的动物模型 感染到： 1. 使用突变体检查 A/E 粘附对 SLT 毒性的影响 在肠细胞消失位点（LEE）。 2. 测试被动施用免疫球蛋白的抗-免疫球蛋白的能力 具有预防肠出血性大肠杆菌疾病的毒性活性。 3. 测试腔内毒素受体类似物预防的能力 肠出血性大肠杆菌疾病。 4. 确定抗生素治疗是有益还是有害 对病程的影响。 5. 检查炎症介质并确定是否可以抗 炎症策略，特别是重组 IL-1 受体 拮抗剂（IL-1ra）和重组TNF结合蛋白（TNF-BP）可以 改变疾病。 6. 使用以下方法检查针对 EHEC 的主动免疫策略： 毒素和肠上皮细胞消失位点基因的产物 （李）。 大肠杆菌菌株RDEC-H19A感染兔子将作为动物 用于这些研究的肠出血性大肠杆菌疾病模型。 RDEC-H19A，由 将 O26:H11 EHEC 的毒素转化噬菌体 H19A 转移至 兔致病性大肠杆菌 RDEC-1，是一种附着和消除 兔病原体。 该菌株产生高水平的志贺样毒素 I (SLT-I)，定植于盲肠和结肠，并在体内诱发肠道疾病 具有与人类肠出血性大肠杆菌病相似的病理变化的兔子。 干预措施将通过以下方式限制 SLT 与内皮细胞的相互作用： 中和血管内的毒素；体内有毒素 肠腔；消除产生毒素的生物体；或抑制 促炎细胞因子的作用。

项目成果

Complete nucleotide sequence and analysis of the locus of enterocyte Effacement from rabbit diarrheagenic Escherichia coli RDEC-1.

兔致泻性大肠杆菌 RDEC-1 肠上皮细胞消失的完整核苷酸序列和位点分析。

• DOI: 10.1128/iai.69.4.2107-2115.2001
• 发表时间: 2001
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Zhu,C;Agin,TS;Elliott,SJ;Johnson,LA;Thate,TE;Kaper,JB;Boedeker,EC
• 通讯作者: Boedeker,EC

Delivery of heterologous protein antigens via hemolysin or autotransporter systems by an attenuated ler mutant of rabbit enteropathogenic Escherichia coli.

通过兔肠致病性大肠杆菌的减毒 ler 突变体通过溶血素或自转运体系统递送异源蛋白抗原。

• DOI: 10.1016/j.vaccine.2005.07.024
• 发表时间: 2006
• 期刊: Vaccine.
• 作者: Zhu,Chengru;Ruiz-Perez,Fernando;Yang,Zhuolu;Mao,Ying;Hackethal,VeronicaL;Greco,KarlaM;Choy,Wendy;Davis,Katherine;Butterton,JoanR;Boedeker,EdgarC
• 通讯作者: Boedeker,EdgarC

LEE-encoded regulator (Ler) mutants elicit serotype-specific protection, but not cross protection, against attaching and effacing E. coli strains.

LEE 编码的调节因子 (Ler) 突变体会​​引发血清型特异性保护，但不会产生交叉保护，以防止大肠杆菌菌株的附着和消失。

• DOI: 10.1016/j.vaccine.2006.10.026
• 发表时间: 2007
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: Zhu,C;Feng,S;Yang,Z;Davis,K;Rios,H;Kaper,JB;Boedeker,EC
• 通讯作者: Boedeker,EC