Mechanisms by which Human Milk Oligosaccharides Protect Against Rotavirus

母乳低聚糖预防轮状病毒的机制

基本信息

批准号：
8298230
负责人：
SHARON Marie DONOVAN
金额：
$ 30.5万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8298230
关键词：
Adult Affect Anatomy Animal Model Attenuated B-Lymphocytes Bacteria Bifidobacterium Binding Breast Feeding Cell Maturation Cell surface Cells Chemicals Child Child Nutrition Complex Data Dendritic Cells Dendritic cell activation Development Diarrhea Diet Digestion Disease Education Environment Epithelial Cells Fermentation Foundations Functional disorder Gastrointestinal tract structure Generations Genes Glycoconjugates Goals Growth Health Health Benefit Health Care Costs Human Human Milk Humoral Immunities Illinois Immune Immune response Immunology In Vitro Incidence Infant Infant formula Inflammatory Response Interdisciplinary Study Intestines Investigation Knowledge Laboratories Lactobacillus Lectin Receptors Ligands Liquid substance Literature Lymphocyte MHC Class II Genes Measures Metagenomics Microbe Microbiology Modeling Morbidity - disease rate Mucosal Immunity Natural Immunity Neonatal Nutrient Nutritional Oligosaccharides Physiological Physiology Polysaccharides Positioning Attribute Principal Investigator Production Property Publishing Quality of life Relative (related person)Research Resistance Rodent Model Rotavirus Rotavirus Infections Severities Small Intestines Source Spleen Structure T-Lymphocyte Universities Vaccinated Vaccination Vaccines Viral Work adaptive immunity base feeding gastrointestinal immune function improved in vitro activity in vivo lacto-N-neotetraose microbial colonization microbial community microbiome mortality neonate pathogen pre-clinical prebiotics prevent programs response

项目摘要

DESCRIPTION (provided by applicant): Human milk contains a remarkable content and structural diversity of oligosaccharides (HMO) that act as a component of the innate immunity by preventing attachment of pathogens to the intestinal lining and by promoting colonization by a healthy microbiota. Despite their recognized importance in neonatal health, research on HMO has been hindered by insufficient quantities to conduct feeding studies. Our long range goal is to understand the mechanisms whereby HMO stimulates neonatal innate and adaptive immunity. We are ideally positioned to undertake these investigations as we have access to large quantities of enzymatically synthesized lacto-N-neotetraose (LNnT) and human milk from which to extract HMO. The objective of this application is to determine how HMO, LNnT, polydextrose and galactooligosaccharide (PDX/GOS) influence activation of dendritic cells (DC) and lymphocyte responses to vaccination against rotavirus (RV) and a subsequent RV challenge in the piglet model. Our central hypothesis is that HMO will enhance immune function by two inter-related mechanisms by directly interacting with DCs and, indirectly, by altering the intestinal microbiota. First, we postulate that HMO glycans interact with c-type lectin receptors on DC, which induce in DC activation and activation of B- and T-lymphocytes. Second, we hypothesize that HMO will promote the growth of Lactobacillus and Bifidobacterium, leading to fermentation of oligosaccharides and enhanced mucosal resistance to RV infection. The specific aims will 1) assess the potential for HMO, LNnT and PDX/GOS to be fermented, to stimulate DC activation and to inhibit RV infectivity and binding in vitro, 2) evaluate the prebiotic actions of oligosaccharides on microbial colonization, mucosal immunity and the response RV vaccination in the piglet, and 3) establish how oligosaccharides alone or in combination with vaccination modulate the response to RV infection in the piglet. The rationale for undertaking this research is that no previous studies have systematically investigated how HMO, LNnT and synthetic prebiotics modulate the microbiota and mucosal immunity. The use of relevant preclinical animal model of RV vaccination and challenge that will further our understanding of the mechanisms underlying the disease and demonstrate the potential for HMOs to improve intestinal function, modulate host-microbe interactions and alter mucosal immunity. Reducing the morbidity and mortality from RV will decrease health care costs and improve the quality of life for infants worldwide.

描述（由申请人提供）：人乳包含寡糖（HMO）的显着含量和结构多样性，通过防止病原体附着在肠道内部并促进健康的微生物群来实现先天免疫的组成部分。尽管它们在新生儿健康中很重要，但对HMO的研究受到了数量不足进行喂养研究的阻碍。我们的远距离目标是了解HMO刺激新生儿先天和适应性免疫的机制。理想情况下，我们可以进行这些研究，因为我们可以获取大量酶合成的乳糖-N-氯糖（LNNT）和人乳以提取HMO的酶。该应用的目的是确定HMO，LNNT，多脱糖和半乳糖醇糖（PDX/GOS）如何影响树突状细胞（DC）（DC）（DC）和淋巴细胞响应对轮状病毒（RV）的疫苗接种和淋巴细胞的反应。我们的中心假设是，HMO通过与DC直接相互作用并间接地通过改变肠道微生物群来通过两种相关机制来增强免疫功能。首先，我们假设HMO Glycans在DC上与C型凝集素受体相互作用，DC诱导了DC激活和B-淋巴细胞的激活。其次，我们假设HMO将促进乳酸杆菌和双歧杆菌的生长，从而导致寡糖发酵并增强对RV感染的粘膜耐药性。具体目的是1）评估发酵HMO，LNNT和PDX/GO的潜力，以刺激DC激活并抑制RV感染性和结合体外的可能性，2）评估寡糖对微生物共同化对单独的益生成型对少量糖的益生元的作用，并与单独的粘膜免疫和反应RV疫苗相结合，以及在OOL中建立了OOL，以及3）OOL，3）OOL，3）piglet，3）。疫苗接种调节小猪中RV感染的反应。进行这项研究的基本原理是，以前的研究没有系统地研究HMO，LNNT和合成益生元如何调节微生物群和粘膜免疫。使用相关的RV疫苗接种和挑战的临床前动物模型，这将进一步了解我们对疾病背后的机制的理解，并证明了HMO提高肠道功能，调节宿主 - 微生物相互作用并改变粘膜免疫力的潜力。减少房车的发病率和死亡率将降低医疗保健成本并改善全球婴儿的生活质量。