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。影响这一年龄组的病原体通常使用凝集素样粘附素粘附在小肠肠细胞和/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。多种因素包括年龄、激素、饮食和特定共生菌群的定植影响上皮糖结合物的表达。我们已经证明，与共生拟杆菌（Bacteroides thetaiotaomicron）定植的成体无菌（gnotobiot）通过上调肠细胞特异性表达1,2聚焦转移酶诱导成熟模式。focusyltransferases将病灶连接到末端半乳糖和n -乙酰氨基葡萄糖残基，从而掩盖上皮表面潜在的配体。这些数据表明，选择共生体定殖可用于治疗性地刺激易感人群中上皮糖结合物表达的有益变化。本研究将验证这样一个假设，即特定的微生物群，特别是B. thetaiotaomicron，可以刺激肠细胞和M细胞顶端表面的糖缀合物的发育，从而降低致病菌、病毒和/或毒素感染/中毒肠上皮的能力。目的1和2将确定B. thetaiotaomicron对小肠和大肠上皮糖结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低聚糖”。目的3将利用霍乱毒素、蓖麻毒素、呼肠孤病毒和鼠伤寒沙门菌感染的成熟小鼠模型具体检验提出的假设。

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.