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: 9884089
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884089
• 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; Cyclic AMP; Cyclic GMP; Cyclic Nucleotides; Data; Dehydration; Diarrhea; Disease; Disease Outbreaks; Enterotoxins; Epithelial; 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; Lead; Lectin; Maintenance; Malabsorption Syndromes; Malnutrition; Mediating; Membrane Glycoproteins; Military Personnel; Molecular; Morbidity - disease rate; Mus; Nature; Pathogenesis; Patients; Planets; Play; Prevention strategy; Production; Recombinants; Research; Resources; Role; Sanitation; Small Intestines; Sodium Chloride; Soldier; Speed; Subfamily lentivirinae; 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; 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.

肠毒素大肠杆菌（ETEC）是非常普遍的原因 军事人员所在的地球有限地区的传染性腹泻 经常部署。在地方性地区，这些病原体是发病率的主要原因 以及幼儿死亡率。与这些有关的急性疾病 病原体可能从轻度腹泻到严重的类似霍乱的疾病 快速脱水。部署到地方性地区的旅行者和军事人员是 高度容易受到ETEC引起的有症状疾病的影响。目前没有疫苗 防止这些感染。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有关 吸收不良和热带肠病，生长阻滞和认知障碍 儿童以及热带吸收不良综合征和肠易激综合症 返回的旅行者。 ETEC由导致盐净出口的肠毒素的产生定义 并将水入肠腔。大多数先前的研究工作几乎都集中在 仅这些导致腹泻的毒素的细胞作用。但是，最近 感染或用毒素治疗后宿主细胞的转录组研究表明 这些肠毒素可能会带来与我们的理解相关的许多附带效果 与急性疾病和后遗症有关的毒力的关键方面 与这些感染有关。拟议的研究将集中于 高度保守的大肠杆菌纤维膜，与一家细胞表面糖蛋白有关 癌胚抗原（CEA），癌腹抗原细胞粘附分子 （CEACAMS）在肠上皮上表达。有趣的是我们的研究 证明这些分子被ETEC热能毒素强烈上调 并且它们可以用作ETEC的受体。因为这些分子发挥了 在组织结构的细胞粘附和维护中的重要作用，调节 它们的表达可能在与这些相关的后遗症中起重要作用 感染。