The dynamics of nasal bacterial ecology and S. aureus antagonism

项目摘要 金黄色葡萄球菌的鼻腔携带者可以作为这种机会性病原体的储存库， 自身感染侵袭性感染的风险增加。我们的长期目标是开发基于益生菌的策略， 阻断耐药性机会致病菌的定植。本项目的目标是确定 与持续的S.金黄色葡萄球菌排除法我们的中心假设是鼻 细菌--如Dolosigranulum和其他尚未鉴定的细菌--可以有效和稳定地表达， 包括S.金黄色鼻疽该项目的基本原理是，最近的横断面研究支持 使用益生菌减少S.金黄色的马车;但要进入下一步，我们必须 阐明鼻腔微生物群的种内和种间动态，并确定是否以及哪些微生物群 可以稳定地排除S。金黄色。这项研究是由我们的团队的独特的专业知识相结合， 微生物组和基因组研究，复杂的生态数据分析，以及新的鼻微生物组-上皮 文化模式，以及我们的团队的独特访问基于人群的鼻腔采样。我们将利用这些 资源，以实现以下具体目标： 目标1。确定与稳定排除沙门氏菌相关的鼻腔鼻窦。健康人金黄色葡萄球菌 成年人了我们将招募1，000名健康的社区居住成年人，并随访180名个体（平等代表）， 每种鼻腔细菌群落的测定），以评估鼻腔细菌生态学的动态 使用基于培养的方法，实时PCR，基因组学和生态分析。 目标2.确定与mupi后持续MRSA非殖民化相关的鼻黏膜- 罗辛治疗。我们将招募并随访100名正在接受去殖民化的MRSA携带者和50名持续性S。 Aim 1的金黄色葡萄球菌鼻载体作为对照12个月，以确定治疗前和治疗后鼻 与非殖民化成功相关的社区，使用基于文化的方法，实时PCR，基因组学， 生态分析。 目标3。证明排除S。金黄色葡萄球菌通过特定的鼻腔社区和个人鼻腔 体外培养的精子。使用目标1和2的样本和鼻细菌分离株，我们将重组 在一种新的微生物组鼻上皮细胞培养模型中的主要鼻腔群落，并验证是否有一些鼻腔复合物， Mensals可以抵抗或排斥S。金黄色。 在这个团队看来，这种方法是创新的，因为它将检查鼻腔微生物组动力学 从绝对丰度的角度来看，它将验证两项大型队列研究的观测结果 在一个新的体外系统中。该项目意义重大，因为它有可能建立一个新的鼻decoloni- 稳定排除S.金黄色葡萄球菌而不选择抗生素耐药性。这项研究将- 评估基因组数据、建立系统模型并分离具有特殊翻译潜力的集合。

PROJECT SUMMARY Nasal carriers of Staphylococcus aureus can serve as reservoirs for this opportunistic pathogen and are them- selves at increased risk for invasive infection. Our long-term goal is to develop probiotic-based strategies to block colonization by antibiotic-resistant opportunistic pathogens. It is the objective of this project to identify nasal commensal bacteria associated with sustained S. aureus exclusion. Our central hypothesis is that nasal commensals—such as Dolosigranulum and other yet-to-be-identified bacteria—can effectively and stably ex- clude S. aureus nasal carriage. The rationale for this project is that recent cross-sectional studies support the potential for using probiotics to reduce S. aureus carriage; but to progress to the next step, it is crucial for us to elucidate the intra- and interspecies dynamics of nasal microbiota and to determine if and which commensals can stably exclude S. aureus. This research is made possible by our team’s unique combination of expertise in microbiome and genomic research, complex ecological data analysis, and novel nasal microbiome-epithelium culture models, as well our team’s unique access to population-based nasal sampling. We will leverage these resources to accomplish the following specific aims: Aim 1. Identify nasal commensals associated with stable exclusion of S. aureus in healthy adults. We will enroll 1,000 healthy community-dwelling adults and follow 180 individuals (with equal represen- tation of each nasal community) over a 12-month period to evaluate the dynamics of nasal bacterial ecology using culture-based methods, real-time PCR, genomics, and ecological analyses. Aim 2. Identify nasal commensals associated with sustained MRSA decolonization after mupi- rocin treatment. We will enroll and follow 100 MRSA carriers undergoing decolonization and 50 persistent S. aureus nasal carriers from Aim 1 as controls for 12-months to determine the pre- and post-treatment nasal communities associated with decolonization success using culture-based methods, real-time PCR, genomics, and ecological analyses. Aim 3. Demonstrate exclusion of S. aureus by specific nasal communities and individual nasal commensals in vitro. Using samples and nasal bacterial isolates from Aims 1 and 2, we will reconstitute the major nasal communities in a novel microbiome-nasal epithelium culture model and verify if some nasal com- mensals can resist or exclude S. aureus. The approach is innovative, in this team’s opinion; because it will examine the nasal microbiome dynamics from the perspective of absolute abundance and it will verify observational results from two large cohort studies in a novel in vitro system. The project is significant because it has the potential to build a new nasal decoloni- zation strategy that can stably exclude S. aureus without selecting for antibiotic resistance. The study will gen- erate genomic data, model systems, and isolate collections with exceptional translational potential.