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Effect of Zinc in Attaching and Effacing E. coli Infection

锌在附着和消除大肠杆菌感染中的作用

基本信息

批准号：
8259806
负责人：
EDGAR C. BOEDEKER
金额：
$ 43.9万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8259806
关键词：
Animal Model Animals Antibiotics Bacteria Bacterial Adhesins Bacterial RNA Binding Biological Assay Body Weight decreased Child Ciprofloxacin Clinical Course of Disease Colitis Cultured Cells DNA Damage DNA Sequence Data Diarrhea Disease Dose Enterocytes Escherichia coli Escherichia coli EHEC Escherichia coli Infections Fluids and Secretions Gene Expression Genes Grant Growth H19 gene Hemolytic-Uremic Syndrome Hour Human Immunoassay In Vitro Infection Intestines Kidney Laboratories Liquid substance Mediating Mitomycins Modeling Molecular Nitric Oxide Operon Oral Oryctolagus cuniculus Pathogenicity Island Pathologic Pathology Printing Process Production Proteins Regimen Reverse Transcription SOS Response Serum zinc level result Severities Shiga Toxin Stress Supplementation Testing Text Time Tissues Toxin Transcription Coactivator Trimethoprim Virulence Virulence Factors Zinc Zinc deficiency enteric pathogen enteropathogenic Escherichia coli foodborne outbreak in vivo pathogen pathogenic Escherichia coli protective effect public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Zinc has been shown to reduce the duration and severity of diarrheal diseases in studies of poor children on several continents. Although these beneficial effects of zinc were first attributed to correction of a zinc deficiency in malnourished children, studies have shown beneficial zinc effects even in children with normal serum zinc levels before study. Studies of enteric pathogens in healthy experimental animals and cultured cell assays have also shown protective effects of zinc in non-zinc deficient animals or conditions. In our laboratories we discovered that zinc strongly inhibits the production of several important virulence factors human enteropathogenic E. coli strains in vitro. We then extended those observations to rabbit EPEC strains and found similar results. Rabbits are natural hosts for EPEC infection, so they constitute a good animal model for us to test zinc efficacy in vivo. Now we also have in vitro data showing that zinc also inhibits virulence in Shiga-toxigenic E. coli (STEC, also known as enterohemorrhagic E. coli, or EHEC). In human-derived EPEC, rabbit EPEC, and STEC, zinc decreases the bacterial production of virulence factors, including adhesins, secreted effector proteins and Shiga toxin (Stx). We propose to further examine the effect of zinc on A/E E.coli infections both in vitro and in vivo. There are 3 specific aims: Specific Aim 1: Determine the direct effects of zinc on attaching and effacing E. coli (including EPEC, REPEC and STEC) in vitro under different growth conditions (and in the presence of antibiotics). Specific Aim 2.: To confirm and further define the effects of zinc on A/E E.coli infection in vivo in ligated rabbit ileal loops, and to examine its effect on STEC infections in these loops. Specific Aim 3: Determine if zinc administration in vivo can protect rabbits against orogastric infections with REPEC and STEC. In addition to examining the effects of zinc on clinical disease course and intestinal pathology, we will also examine if zinc can protect against extra-intestinal pathology induced by STEC (especially kidney damage). For these studies we will use a new model of hemorrhagic colitis (HC) and hemolytic uremic syndrome (HUS) which develops in Dutch Belted rabbits challenged with REPEC strains expressing Stx1 or Stx2. PUBLIC HEALTH RELEVANCE: "Attaching and Effacing E. coli" includes 2 groups of diarrhea-producing E. coli, enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC, also called Shiga toxigenic E. coli, or STEC). EHEC, such as strain O157:H7, has received wide publicity due to foodborne outbreaks. Zinc inhibits the virulence of both of these groups of E. coli, and we wish to study zinc further to see if it could be used as a treatment for these infections.

描述（由申请人提供）：针对几大洲贫困儿童的研究表明，锌可以减少腹泻病的持续时间和严重程度。尽管锌的这些有益作用最初归因于纠正营养不良儿童的锌缺乏症，但研究表明，即使在研究之前血清锌水平正常的儿童中，锌也具有有益的作用。对健康实验动物肠道病原体的研究和培养细胞测定也显示了锌对非缺锌动物或状况的保护作用。在我们的实验室中，我们发现锌在体外强烈抑制人类肠道致病性大肠杆菌菌株中几种重要毒力因子的产生。然后，我们将这些观察结果扩展到兔子 EPEC 品系，并发现了类似的结果。兔子是EPEC感染的天然宿主，因此为我们测试体内锌功效提供了良好的动物模型。现在我们还有体外数据表明，锌还可以抑制志贺毒素大肠杆菌（STEC，也称为肠出血性大肠杆菌，或 EHEC）的毒力。在人源 EPEC、兔 EPEC 和 STEC 中，锌可降低细菌毒力因子的产生，包括粘附素、分泌效应蛋白和志贺毒素 (Stx)。我们建议进一步研究锌对体外和体内 A/E 大肠杆菌感染的影响。有 3 个具体目标：具体目标 1：确定锌在不同生长条件（以及存在抗生素的情况下）体外对大肠杆菌（包括 EPEC、REPEC 和 STEC）附着和消除的直接影响。具体目标 2.：确认并进一步明确锌对结扎兔回肠环体内 A/E 大肠杆菌感染的影响，并检查其对这些环中 STEC 感染的影响。具体目标 3：确定体内锌给药是否可以保护兔子免受 REPEC 和 STEC 的口胃感染。除了研究锌对临床病程和肠道病理的影响外，我们还将研究锌是否可以预防 STEC 引起的肠外病理（特别是肾脏损伤）。在这些研究中，我们将使用一种新的出血性结肠炎 (HC) 和溶血性尿毒症综合征 (HUS) 模型，该模型是在受到表达 Stx1 或 Stx2 的 REPEC 菌株攻击的荷兰带兔中开发的。公众健康相关性：“附着和消除大肠杆菌”包括 2 类产生腹泻的大肠杆菌：肠病性大肠杆菌 (EPEC) 和肠出血性大肠杆菌 (EHEC，也称为志贺毒素大肠杆菌，或 STEC)。 EHEC，例如 O157:H7 菌株，由于食源性疫情而受到广泛关注。锌可以抑制这两类大肠杆菌的毒力，我们希望进一步研究锌，看看它是否可以用来治疗这些感染。