Modeling Staphylococcus aureus antagonism in pediatric nasal communities

模拟儿科鼻群中金黄色葡萄球菌的拮抗作用

• 批准号: 9266364
• 负责人: Cindy Liu
• 金额: $ 19.64万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-25 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266364
• 关键词: Adult; Age; Antibiotic Resistance; Antibiotics; Bacteria; Biological Models; Child; Childhood; Clinical Microbiology; Coculture Techniques; Collection; Communicable Diseases; Communities; Development; Dose; Effectiveness; Environment; Epithelium; Exclusion; Frequencies; Future; Goals; Habitats; Human; Individual; Infant; Infection; Interruption; Knowledge; Lactic acid; Life; Measures; Methicillin Resistance; Methods; Microbe; Mission; Modeling; Mupirocin; Nasal Epithelium; Nasal cavity; National Institute of Allergy and Infectious Disease; Nature; Nose; Outcome Study; Population; Predisposition; Prevention strategy; Price; Probiotics; Productivity; Public Health; Research; Resistance; Risk; Risk Factors; Role; Sampling; Science; Scientist; Staphylococcus aureus; Structure; Symbiosis; Systems Biology; Testing; Vagina; Virulence; Work; base; commensal microbes; genomic epidemiology; in vitro Model; innovation; insight; microbial; microbiome; microbiota; multi-drug resistant pathogen; novel; novel strategies; pathogen; prevent; public health relevance; stem; transmission process; trend

 DESCRIPTION (provided by applicant): The nasal cavity is an important niche for Staphylococcus aureus. Young children-particularly those age 3 or younger-are more likely to be colonized by S. aureus than older children or adults. S. aureus nasal colonization significantly increases the risk for subsequent infection, but decolonization strategies for children are limited, and mupirocin resistance is emerging. In recent years, S. aureus infection rates have also steadily risen in the pediatric population, despite opposing trends in adults. Better preventative strategies against S. aureus are urgently needed to reduce pediatric infections. Our long-term goal is to develop probiotic-based strategies to decrease S. aureus colonization, transmission, and infection in children. To achieve this, we need to better understand the dynamics and determinants of pediatric nasal microbiota. The overall objective of this proposal is to identify commensals that can competitively exclude S. aureus in the pediatric nasal environment. The central hypothesis, based on our preliminary studies, is that competitive exclusion from non-pathogenic nasal commensals, such as Dolosigranulum, can persistently resist S. aureus colonization. The rationale for the proposed research is that a better understanding of nasal microbiota stability and succession, combined with experimental testing of how Dolosigranulum and other commensals interact with S. aureus will provide important insights into the potential effectiveness of nasal probiotics. The study's hypothesis wil be tested through two specific aims: Aim 1: Determine if children with high absolute abundances of specific nasal commensals have lower risk of carrying S. aureus in the first year of life; and Aim 2: Empirically determine Dolosigranulum's ability to competitively exclude S. aureus in a novel epithelium-microbiome culture model. Aim 1 will be accomplished using an existing collection of longitudinal nasal samples from infants in the first year of life (n = 203). The baseline (i.e., month 1) sample will be characterized by absolute abundance-based microbiome analysis to identify infants with Dolosigranulum- or S. aureus-dominated nasal community state type (CST). The microbial succession of 30 infants with each CST at baseline will be characterized to determine the dynamics of these CSTs. To assess nasal bacterial competition experimentally, Aim 2 will construct an epithelium-microbiome model using samples with select CSTs from Aim 1, which will undergo direct challenges with S. aureus and other nasal CSTs. The approach is innovative, in this team's opinion, because it will construct and validate a novel in vitro model system to recapitulate observed nasal CSTs and enable empiric testing of our competitive-exclusion hypothesis in a mixed culture environment. The proposed research is significant, because it is a proof-of-principle study of nasal probiotics against S. aureus. Importantly, the project will generate an effective model system for future host-microbe and microbe-microbe studies that will accelerate the discovery of new ways to prevent S. aureus colonization and infection.

 描述（由申请人提供）：鼻腔是金黄色葡萄球菌的重要生态位。年幼的儿童，特别是3岁或3岁以上的儿童，更有可能被S。金黄色葡萄球菌比年龄较大的儿童或成人。S.金黄色葡萄球菌鼻腔定植显著增加了随后感染的风险，但儿童的定植策略有限，并且正在出现莫匹罗星耐药性。近年来，S.金黄色葡萄球菌感染率在儿童人群中也稳步上升，尽管在成人中的趋势相反。更好的预防策略对S。金黄色葡萄球菌，迫切需要减少儿科感染。我们的长期目标是开发基于益生菌的策略来减少S。金黄色葡萄球菌定植、传播和儿童感染。为了实现这一目标，我们需要更好地了解儿科鼻腔微生物群的动态和决定因素。本提案的总体目标是确定能够在竞争中排除S的企业。金黄色葡萄球菌在小儿鼻环境中。基于我们的初步研究，中心假设是来自非致病性鼻粘膜的竞争性排斥，如Dolosigranulum，可以持续抵抗S。金黄色葡萄球菌定植。这项研究的基本原理是，更好地了解鼻腔微生物群的稳定性和连续性，结合实验测试Dolosigranulum和其他微生物如何与S。金黄色葡萄球菌将提供重要的见解鼻益生菌的潜在有效性。该研究的假设将通过两个特定的目标进行测试：目标1：确定特定鼻腔分泌物绝对丰度高的儿童是否具有较低的携带S的风险。目的2：经验性地确定Dolosigranulum竞争性排除金黄色葡萄球菌的能力。金黄色葡萄球菌在一种新的上皮-微生物组培养模型。目标1将使用现有的收集纵向鼻样本的婴儿在生命的第一年（n = 203）。基线（即，第1个月）的样本将通过基于绝对丰度的微生物组分析来表征，以鉴定患有Dolosigranulum或S.金黄色为主的鼻腔社区状态型（CST）。将对基线时每种CST的30名婴儿的微生物演替进行表征，以确定这些CST的动力学。为了通过实验评估鼻内细菌竞争，Aim 2将使用来自Aim 1的选定CST样本构建上皮-微生物组模型，该模型将接受S.金黄色葡萄球菌和其他鼻CST。在这个团队看来，这种方法是创新的，因为它将构建和验证一种新的体外模型系统，以概括观察到的鼻CST，并在混合培养环境中对我们的竞争排斥假说进行经验性检验。这项研究意义重大，因为它是一项鼻用益生菌对抗沙门氏菌的原理验证研究。金黄色。重要的是，该项目将为未来的宿主-微生物和微生物-微生物研究产生一个有效的模型系统，这将加速发现预防沙门氏菌的新方法。金黄色葡萄球菌定植和感染。