Polymicrobial oral bacterial host interactions in a high throughput model

高通量模型中多种微生物口腔细菌宿主相互作用

• 批准号: 8828875
• 负责人: Christina Igboin
• 金额: $ 38.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828875
• 关键词: Adult; Affect; Animal Model; Animals; Attenuated; Bacteria; Benign; Biological Models; Chronic Disease; Collaborations; Communities; Complex; DNA; Data; Disease; Drosophila genus; Drosophila melanogaster; Epidemiologic Studies; Etiology; Gene Expression; Gene Expression Profile; Health; Human; Immune response; Individual; Infection; Integration Host Factors; Lead; Maps; Mediating; Microbe; Mind; Modeling; Molecular Profiling; Monitor; Nature; Oral; Oral Microbiology; Pathogenesis; Pathway interactions; Pattern; Periodontitis; Porphyromonas gingivalis; Positioning Attribute; Prevalence; Probiotics; RNA Interference; Research; Resistance; Role; Sampling; Shapes; Side; Soft Tissue Infections; System; Technology; Testing; Therapeutic Intervention; Translations; Virulence; Virulent; Widespread Disease; Work; base; candidate selection; clinically relevant; deep sequencing; epidemiologic data; feeding; genetic analysis; in vivo; insight; knock-down; knockout gene; microbial; microbial community; microbial host; mouse model; mutant; next generation sequencing; oral bacteria; oral commensal; pathogen; prevent; public health relevance; research study; response; transcriptome sequencing

DESCRIPTION (provided by applicant): Chronic periodontitis affects half of adults in the US, and pathogenesis results from polymicrobial---host interactions that are not completely understood. Using next generation sequencing technology many new candidate species have been associated with disease, and others with health. But epidemiologic data does not establish causality, so the role of most of these species in periodontitis remains hypothetical. In attempting to understand pathogenesis, a holistic view that includes contributions from both microbes and host is needed. If we are to unravel host interactions with highly complex bacterial communities, we will need to systematically screen in a high throughput system that models host---microbe interplay. And for clinical relevance it is important to ground studies in human epidemiologic data to target candidates from the large number of possible combinations. Deep---sequencing data generated by our group on species prevalence in health and disease, and co---occurrence in individuals, will be used to guide the selection of candidates for the proposed studies. The genetically tractable animal, Drosophila melanogaster, shares many mammalian innate immune response features, has been well developed as a model host---microbe system, and has been adapted for oral microbiology research by our group. The natural infection (feeding) model provides a high--- throughput, powerful approach that allows us to detect and understand in vivo interactions between oral polymicrobial communities and the host. The Drosophila model also allows comprehensive and simultaneous monitoring of bacteria and host gene expression profiles during infection, using RNA---seq. The aims of this project are to identify virulent and beneficial oral species and to identify virulence---enhancing and ---attenuating interactions between oral species, in the Drosophila model. Then candidate bacterial and host factors that are important for these interactions will be identified using RNA-- seq, and tested using Drosophila gene knockout mutants and/or RNAi knock---down lines. This project will be a considerable step forward in understanding the pathogenesis of periodontitis in a holistic view that includes interactions of microbes with one another and the host. Ultimately this work could lead to therapeutic interventions on the host or bacterial side. If beneficial interactions are discovered, translation to chairside as probiotic therapies could occur very rapidly. Strategies to target virulence mechanisms would have a longer horizon, but are highly likely to be suggested by the project.

描述（由申请人提供）：慢性牙周炎影响了美国的一半成年人，而发病机理是由多数型 - 宿主相互作用引起的，这些相互作用尚未完全理解。使用下一代测序技术，许多新候选物种与疾病以及其他疾病有关。但是流行病学数据并未确定因果关系，因此大多数这些物种在牙周炎中的作用仍然假设。在尝试理解发病机理时，需要一种整体观点，其中包括微生物和宿主的贡献。如果我们要与高度复杂的细菌群落揭开宿主的相互作用，我们将需要系统地筛选高吞吐量系统，该系统模拟宿主的模型---微生物相互作用。对于临床相关性，重要的是在人类流行病学数据中进行研究，以针对大量可能组合的候选者。深层---我们小组在健康和疾病中的物种患病率以及个体中发生的物种患病率产生的测序数据将用于指导拟议研究的候选人的选择。遗传上可牵引的动物，果蝇Melanogaster具有许多哺乳动物的先天免疫反应特征，已作为模型宿主 - - 微生物系统得到了很好的发展，我们小组已将其用于口腔微生物研究。自然感染（喂养）模型提供了一种高 - 吞吐量，有力的方法，使我们能够检测和理解口腔多生物群落和宿主之间的体内相互作用。果蝇模型还允许使用RNA --- seq在感染过程中全面和同时监测细菌和宿主基因表达谱。该项目的目的是识别毒力和有益的口腔物种并确定毒力 - 增强和 - - 削弱了果蝇模型中口腔物种之间的相互作用。然后，将使用RNA鉴定出对这些相互作用很重要的候选细菌和宿主因素 - Seq，并使用果蝇基因基因敲除突变体和/或RNAi敲击 - - 下线进行了测试。在整体观点中，该项目将是了解牙周炎发病机理的一步，其中包括微生物与彼此的相互作用和宿主的相互作用。最终，这项工作可能会导致宿主或细菌方面的治疗干预措施。如果发现有益的相互作用，则可以将益生菌疗法转移到椅子方面。靶向毒力机制的策略将具有更长的视野，但是该项目很可能会提出。