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）：已证明锌可以减少腹泻疾病的持续时间和严重程度。尽管锌的这些有益作用首先归因于营养不良儿童中锌缺乏症的校正，但研究表明，即使在研究前血清锌水平正常的儿童中，锌的影响也有益。在健康的实验动物和培养的细胞测定中对肠道病原体的研究也显示了锌在非锌不足动物或条件下的保护作用。在我们的实验室中，我们发现锌在体外强烈抑制了人类肠病大肠杆菌菌株的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EPEC菌株，并发现了相似的结果。兔子是EPEC感染的天然宿主，因此它们构成了我们在体内测试锌功效的好动物模型。现在，我们还拥有体外数据，表明锌还抑制了shiga-toxigenic E. coli（STEC，也称为肠ho骨大肠杆菌或EHEC）中的毒力。在人类衍生的EPEC，兔EPEC和STEC中，锌降低了毒力因子的细菌产生，包括粘附素，分泌的效应蛋白和志贺毒素（STX）。我们建议进一步检查锌对体外和体内A/E e.coli感染的影响。有3个具体目的：具体目标1：确定锌对在不同生长条件下（以及在抗生素存在下）的体外体外附着和排出的大肠杆菌（包括EPEC，REPEC和STEC）的直接影响。具体目标2。：要确认并进一步定义锌在带状的兔回肠环中体内A/e e.coli感染的影响，并检查其对这些环中STEC感染的影响。特定目的3：确定体内锌给药是否可以保护兔子免受重复和STEC的外胃感染。除了检查锌对临床疾病病程和肠道病理学的影响外，我们还将检查锌是否可以预防由STEC诱导的肠外病理（尤其是肾脏损害）。在这些研究中，我们将使用新的出血性结肠炎（HC）和溶血性尿毒症综合征（HUS）的新模型，该模型在荷兰腰带兔子中发展，该兔子受到表达STX1或STX2的repec菌株的挑战。公共卫生相关性：“附着和剥落大肠杆菌”包括2组腹泻的大肠杆菌，肠发育大肠杆菌（EPEC）和肠haporhagic E. coli（EHEC，也称为shiga toxigaic E. coli oil oil or ot stec）。 EHEC，例如O157：H7的应变，由于食源性爆发而受到广泛的宣传。锌抑制了这两组大肠杆菌的毒力，我们希望进一步研究锌，以查看是否可以用作这些感染的治疗方法。