Microbiome and E. coli O157:H7 infection of human gut tissue

人体肠道组织的微生物组和大肠杆菌 O157:H7 感染

基本信息

批准号：
9764263
负责人：
Alison A. Weiss
金额：
$ 40.13万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9764263
关键词：
Actins Acute Kidney Failure Adult Animal Model Animals Antibiotic Therapy Antibiotics Bacteria Bacteriophages Biological Models Child Clustered Regularly Interspaced Short Palindromic Repeats Complication DNA Disease Disease Outcome Disease Progression Environment Epithelial Escherichia coli Escherichia coli EHEC Escherichia coli Infections Escherichia coli O157:H7 F-Actin Genetic Engineering Germ-Free Health Hemolytic-Uremic Syndrome Hemorrhagic colitis Hour Human In Vitro Incidence Individual Infection Inflammation Injections Integration Host Factors Intestines Knowledge Life Lytic Phase Modeling Mucous body substance Mus Organoids Outcome Pathogenicity Patients Pre-Clinical Model Predisposition Process Production Rage Reporting Resistance Role Safety Severity of illness Shiga Toxin Source Stains Stem cells Surface Antigens System Technology Testing Therapeutic Therapeutic Intervention Tissue Model Tissue Sample Tissues Translating Up-Regulation Virulence Factors commensal bacteria embryonic stem cell experience foodborne illness gut microbiota human disease human pathogen human tissue microbial microbial host microbiome microbiome alteration microorganism interaction pathogen pathogenic Escherichia coli pathogenic bacteria prevent resident commensals response stem cell biology

项目摘要

Project Summary/Abstract Shiga toxin producing E. coli (STEC), including O157:H7, are a leading cause of food-borne illnesses, causing about 100,000 cases of watery and bloody diarrhea annually in the US. About 10% of cases progress to the life-threatening complication, hemolytic uremic syndrome (HUS). For reasons that are not clear, young children are more likely to develop HUS than adults, and HUS is the most common cause of acute kidney failure in children. Currently there is no treatment for STEC. Furthermore, antibiotics induce STEC to produce higher quantities of Shiga toxin, and antibiotic treatment is associated with increased incidence of severe disease. A serious limitation has been the lack of good animal models. Mice are not susceptible to STEC or Shiga toxin when introduced into the intestinal tract. We have now shown that stem cell derived ‘induced human intestinal organoids’ (iHIOs) are sensitive to E. coli O157:H7 and Shiga toxin, and thus represents the first tractable model system to study human disease. This proposal will test the hypotheses that iHIOs can be used to identify microbial and host factors that influence infection by STEC: Aim 1 will test role of antibiotics in preventing or enhancing disease. Aim 2 will examine the role of the microbiome in influencing disease progression. Aim 3 will determine if agents reported to down-regulate O157:H7 virulence factor expression can impact disease outcome by preventing intestinal damage. These studies will increase our understanding of human STEC infection and could provide a simple experimental system to assess potential therapeutic interventions for safety and efficacy in humans.

项目概要/摘要产生志贺毒素的大肠杆菌 (STEC)，包括 O157:H7，是食源性疾病的主要原因，美国每年约有 100,000 例水样腹泻和血性腹泻，其中约 10% 的病例出现进展。导致危及生命的并发症，溶血性尿毒症综合征（HUS），原因尚不清楚，年轻人。儿童比成人更容易患 HUS，而 HUS 是急性肾病的最常见原因目前尚无治疗 STEC 的方法，而且抗生素会诱导 STEC 的产生。志贺毒素含量较高，抗生素治疗与严重志贺毒素发病率增加有关疾病。一个严重的限制是缺乏良好的动物模型，小鼠不易受到 STEC 或 STEC 的影响。我们现在已经证明干细胞来源的“诱导”志贺毒素。人肠道类器官（iHIO）对大肠杆菌 O157:H7 和志贺毒素敏感，因此代表该提案将测试 iHIO 的假设。用于识别影响 STEC 感染的微生物和宿主因素：目标 1 将测试抗生素在预防或增强疾病方面的作用。目标 2 将研究微生物组在影响疾病进展中的作用。目标 3 将确定据报告下调 O157:H7 毒力因子表达的药物是否可以通过预防肠道损伤来影响疾病结果。这些研究将增加我们对人类 STEC 感染的了解，并可以提供一个简单的方法评估人类潜在治疗干预措施安全性和有效性的实验系统。