Epithelial Glycoconjugates as Barriers against Enteric Infections

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。影响该年龄组的病原体通常使用凝集素样粘附素来粘附在小肠上皮细胞和/或M细胞上表达的宿主糖蛋白和糖脂上。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。多种因素，包括年龄、激素、饮食和特定肠道微生物群落的定植影响上皮糖缀合物的表达。我们已经表明，定殖的成年无菌（gnotobiotic）与多形拟杆菌诱导成熟的模式，通过上调肠细胞特异性表达的1，2岩藻糖基转移酶。岩藻糖基转移酶将岩藻糖连接至末端半乳糖和N-乙酰基-葡糖胺残基，从而掩蔽上皮表面上的潜在配体。这些数据表明，用选择的细菌定殖可用于治疗性地刺激易感人群中上皮糖缀合物表达的有益变化。该提议将检验选择微生物区系，特别是B的假设。多形微粒刺激肠上皮细胞和M细胞顶面上糖缀合物的发育，这降低了病原性细菌、病毒和/或毒素感染/毒害肠上皮的能力。目标1和2将决定B的全部影响。多形核团对小肠和大肠中上皮糖缀合物的表达和可及性的影响。这些目标直接响应RFA HD 08-004（项目5）“调查肠细胞表面的糖缀合物，以发现可能作为致病性和非致病性细菌配体的寡糖。“目标3将使用霍乱毒素、蓖麻毒素、呼肠孤病毒和鼠伤寒沙门氏菌感染的成熟小鼠模型来具体测试所提出的假设。

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.