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（由适用提供）：鼻腔是金黄色葡萄球菌的重要利基市场。尤其是3岁或年轻的孩子比大儿童或成年人更有可能被金黄色葡萄球菌殖民。金黄色葡萄球菌鼻定植显着增加了随后感染的风险，但儿童非殖民化策略有限，而莫皮罗蛋白的耐药性也出现了。近年来，尽管成年人趋势相反，但小儿种群中的金黄色葡萄球菌感染率也稳定下降。迫切需要针对金黄色葡萄球菌的更好的预防性策略来减少小儿感染。我们的长期目标是制定基于益生菌的策略，以减少儿童的金黄色葡萄球菌定植，传播和感染。为了实现这一目标，我们需要更好地了解小儿鼻菌群的动态和决定。该提案的总体目的是确定可以在小儿鼻环境中竞争性地排除金黄色葡萄球菌的共生。基于我们的初步研究的中心假设是，竞争性排除在非致病性鼻发育中，例如dolosigranulum，可以持续抵抗金黄色葡萄球菌定植。拟议的研究的理由是，更好地了解鼻菌群稳定性和成功，结合了对多洛氏菌和其他共生与金黄色葡萄球菌如何相互作用的实验测试，将为鼻益生菌的潜在有效性提供重要的见解。该研究的假设将通过两个具体的目的进行检验：目标1：确定具有特定特定鼻气质的绝对抽象的儿童是否在生命的第一年携带金黄色葡萄球菌的风险较低；和目标2：从经验上确定多洛氏菌在新型上皮 - 微生物组培养模型中有能力排除金黄色葡萄球菌的能力。 AIM 1将使用在生命的第一年中的现有纵向鼻样样本集合来完成（n = 203）。基线（即第1个月）样本将以基于绝对抽象的微生物组分析为特征，以鉴定具有dolosigranulum-或S.金黄色葡萄球菌主导的鼻社区状态类型（CST）的婴儿。在基线时，每个CST的30名婴儿的微生物成功将表征以确定这些CST的动力学。为了通过实验评估鼻细菌竞争，AIM 2将使用来自AIM 1的选择CST的样品构建上皮 - 微生物组模型，该模型将对金黄色葡萄球菌和其他鼻CST进行直接挑战。在这个团队的看来，这种方法具有创新性，因为它将构建和验证一种新型的体外模型系统，以概括观察到的鼻CST并在混合文化环境中对我们的竞争性排斥假设进行经验性测试。拟议的研究很重要，因为它是针对金黄色葡萄球菌的鼻益生菌的原则研究。重要的是，该项目将生成一个有效的模型系统，用于未来的宿主微叶和微生物微生物研究，该研究将加速发现新方法来防止金黄色葡萄球菌殖民化和感染。