Molecular Pathogenesis of Enterotoxigenic Escherichia coli Infections

产肠毒素大肠杆菌感染的分子发病机制

• 批准号: 10553173
• 负责人: James Michael Fleckenstein
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553173
• 关键词: Acute; Adhesions; Animals; Antibodies; Architecture; Archives; Area; Bacteria; Bacterial Adhesins; Bacterial Adhesion; Bacterial Toxins; Bangladesh; Binding; Biological Assay; Biopsy; CEACAM1; CEACAM5 gene; CEACAM7 gene; Carcinoembryonic Antigen; Cause of Death; Cell Adhesion; Cell Adhesion Molecules; Cells; Child; Cholera; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Cyclic AMP; Cyclic GMP; Cyclic Nucleotides; Data; Dehydration; Diarrhea; Disease; Disease Outbreaks; Enterotoxins; Epithelial Cells; Epithelium; Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Escherichia coli heat-labile toxin; Family; Genetic Engineering; Genetic Transcription; Growth; Human; Impaired cognition; In Vitro; Individual; Infection; Infection prevention; Intestines; Ion Channel; Irritable Bowel Syndrome; Kinetics; Laboratories; Lectin; Maintenance; Malabsorption Syndromes; Malnutrition; Mediating; Membrane Glycoproteins; Military Personnel; Molecular; Morbidity - disease rate; Mus; Nature; Pathogenesis; Patients; Planets; Play; Predisposition; Prevention strategy; Production; Recombinants; Research; Resource-limited setting; Role; Sanitation; Small Intestines; Sodium Chloride; Soldier; Speed; Symptoms; Testing; Therapeutic; Tissues; Toxin; Transgenic Mice; Tropical sprue; United States; Vaccines; Veterans; Virulence; Water; apical membrane; carcinoembryonic antigen-related cell adhesion molecules; design; diarrheal disease; enterotoxigenic Escherichia coli; experience; gut colonization; in vivo; insight; intestinal epithelium; lentivirally transduced; low and middle-income countries; monolayer; mortality; pathogen; prevent; receptor; response; stem cells; therapy development; transcriptome; transcriptome sequencing; treatment strategy; type 1 fimbriae; type 1 fimbriae receptor; vaccine development

Enterotoxigenic Escherichia coli (ETEC) are an extraordinarily common cause of infectious diarrhea in resource limited areas of the planet where military personnel are frequently deployed. In endemic areas these pathogens are a major cause of morbidity as well as mortality in young children. The acute illness associated with these pathogens may range from mild diarrhea to severe, cholera-like disease associated with rapid dehydration. Travelers and military personnel deployed to endemic regions are highly susceptible to symptomatic illness caused by ETEC. Currently there is no vaccine to prevent these infections. In addition to the acute illness these pathogens are associated with a number of important but poorly understood sequelae including malabsorption and tropical enteropathy, growth stunting, and cognitive impairment in children as well as tropical malabsorption syndromes and irritable bowel syndrome in returning travelers. ETEC are defined by the production of enterotoxins that lead to net export of salt and water into the intestinal lumen. Most prior research effort has focused almost exclusively on the cellular effects of these toxins that lead to diarrhea. However, recent transcriptome studies of host cells following infection or treatment with toxin suggest that these enterotoxins may impart many collateral effects relevant to our understanding of key aspects of virulence associated with acute illness as well as the sequelae associated with these infections. The proposed studies will focus on the interaction of highly conserved E. coli fimbriae with a family of cell surface glycoproteins related to carcinoembryonic antigen (CEA), the carcinoembryonic antigen cell adhesion molecules (CEACAMs) that are expressed on intestinal epithelia. Interestingly our studies demonstrate that these molecules are strongly up-regulated by ETEC heat-labile toxin and that they may serve as a receptor for ETEC. Because these molecules play essential roles in cellular adhesion and maintenance of tissue architecture, modulation of their expression could play important roles in the sequelae associated with these infections.

产肠毒素大肠杆菌（ETEC）是一种非常常见的原因， 在地球上资源有限的地区， 经常部署。在流行地区，这些病原体是发病的主要原因 以及幼儿的死亡率。与此相关的急性疾病 病原体的范围从轻度腹泻到严重的霍乱样疾病， 快速脱水部署到流行地区的旅行者和军事人员 对ETEC引起的症状性疾病高度敏感。目前还没有疫苗 来预防这些感染。除了急性疾病，这些病原体是 与许多重要但知之甚少的后遗症相关，包括 吸收不良和热带肠病，生长发育迟缓，认知障碍， 儿童以及热带吸收不良综合征和肠易激综合征， 归来的旅人 ETEC的定义是产生导致盐净出口的肠毒素 和水进入肠腔。大多数先前的研究工作几乎集中在 专门研究导致腹泻的毒素对细胞的影响。但最近的 感染或毒素处理后宿主细胞的转录组研究表明， 这些肠毒素可能会带来许多与我们的理解相关的附带影响， 与急性疾病相关的毒力的关键方面以及 与这些感染有关。拟议的研究将侧重于以下方面的相互作用： 高度保守的E.大肠杆菌菌毛与一个家庭的细胞表面糖蛋白相关 癌胚抗原（CEA），癌胚抗原细胞粘附分子 在肠上皮细胞上表达的CEACAMs。有趣的是， 表明这些分子被ETEC不耐热毒素强烈上调 并且它们可以作为ETEC的受体。因为这些分子 在细胞粘附和维持组织结构、调节 它们的表达可能在与这些相关的后遗症中发挥重要作用， 感染.