Epithelial Glycoconjugates as Barriers against Enteric Infections

上皮糖复合物作为肠道感染的屏障

基本信息

批准号：
8511759
负责人：
LYNN BRY
金额：
$ 37.33万
依托单位：
WADSWORTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8511759
关键词：
Adult Affect Age Animals Antigens Apical Bacteria Bacterial Adhesins Bacteroides Bacteroides thetaiotaomicron Binding Cause of Death Cellular biology Child Childhood Cholera Toxin Clinical Clinical Microbiology Communicable Diseases Complex Core Facility Data Developing Countries Development Diet Digestive System Disorders Disease Embryonic Development Enteral Enterocytes Epithelial Epithelial Cells Epitopes Fucose Fucosyltransferase Galactose Gastrointestinal tract structure Germ-Free Glucosamine Glycoconjugates Glycolipids Glycoproteins Gnotobiotic Health Helicobacter pylori Hormones Hospitals In Vitro Infection Intestines Intoxication Laboratories Large Intestine Lectin Ligands Link M cell Masks Microspheres Mono-S Morbidity - disease rate Mus New York Newborn Infant Oligosaccharides Oryctolagus cuniculus Particle Size Pathologist Pathology Pattern Physician Executives Population Predisposition Process Production Relative (related person)Reovirus Research Research Personnel Research Project Grants Resources Ricin Role Salmonella typhimurium Scientist Secretor blood group alpha-2-fucosyltransferase Severities Small Intestines Stomach Suckling Animals Surface Surveys Testing Tissues Toxin Tropism Virus Woman Work age group commensal microbes enteric pathogen glycosylation in vivo in vivo Model intestinal epithelium mature animal medical schools member mortality mouse model pathogen pathogenic bacteria prevent professor receptor

项目摘要

DESCRIPTION (provided by applicant): Enteric infections remain a leading cause of morbidity and mortality in children under the age of five. Pathogens affecting this age group commonly use lectin-like adhesins to adhere to host glycoproteins and glycolipids expressed on small intestinal enterocytes and/or M cells. The expression patterns of these glycoconjugates can thus impact the host's underlying susceptibility to infection. A variety of factors including age, hormones, diet, and colonization with specific commensal microflora impacts epithelial glycoconjugate expression. We have shown that colonization of adult germ-free (gnotobiotic) with the commensal Bacteroides thetaiotaomicron induces a mature pattern by up-regulating enterocyte-specific expression of a 1,2 fucosyltransferase. Fucosyltransferases link fucose to terminal galactose and N-acetyl-glucosamine residues, and thereby mask potential ligands on epithelial surfaces. These data suggest that colonization with select commensals could be used to therapeutically stimulate beneficial changes in epithelial glycoconjugate expression in susceptible populations. This proposal will test the hypothesis that select microflora, notably B. thetaiotaomicron, stimulate the development of glycoconjugates on the apical surfaces of enterocytes and M cells that reduces the capacity of pathogenic bacteria, viruses and/or toxins to infect/intoxicate the intestinal epithelium. Aims 1 and 2 will determine the full impact of B. thetaiotaomicron on expression and accessibility of epithelial glycoconjugates in the small and large intestines. These aims are directly responsive to RFA HD 08-004 (Item 5) "Surveying glycoconjugates on the surface of enterocytes to discover oligosaccharides that may serves as ligands for pathogenic and non-pathogenic bacteria." Aim 3 will specifically test the proposed hypothesis using well-established mouse models of cholera toxin, ricin toxin, reovirus and Salmonella typhimurium infection.

描述（由申请人提供）：肠道感染仍然是五岁以下儿童发病和死亡的主要原因。影响该年龄段的病原体通常使用凝集素样粘附素来粘附小肠肠上皮细胞和/或 M 细胞上表达的宿主糖蛋白和糖脂。因此，这些糖缀合物的表达模式可以影响宿主对感染的潜在易感性。包括年龄、激素、饮食和特定共生微生物群落定植在内的多种因素都会影响上皮糖复合物的表达。我们已经证明，通过上调肠细胞特异性 1,2 岩藻糖基转移酶的表达，共生多形拟杆菌 (Bacteroides thetaiotaomicron) 定植成体无菌（无菌）可诱导成熟模式。岩藻糖基转移酶将岩藻糖连接到末端半乳糖和 N-乙酰基-葡萄糖胺残基，从而掩盖上皮表面上的潜在配体。这些数据表明，选择共生体的定植可用于治疗性刺激易感人群上皮糖缀合物表达的有益变化。该提案将检验以下假设：选择微生物群，特别是 B. thetaiotaomicron，刺激肠上皮细胞和 M 细胞顶端表面糖复合物的发育，从而降低病原细菌、病毒和/或毒素感染/中毒肠上皮的能力。目标 1 和 2 将确定 B. thetaiotaomicron 对小肠和大肠中上皮糖复合物的表达和可及性的全面影响。这些目标直接响应 RFA HD 08-004（第 5 项）“调查肠上皮细胞表面的糖缀合物，以发现可作为致病性和非致病性细菌配体的寡糖。”目标 3 将使用成熟的霍乱毒素、蓖麻毒素、呼肠孤病毒和鼠伤寒沙门氏菌感染小鼠模型专门测试所提出的假设。