Probing Polymicrobial Synergy Using High Throughput Genomics

利用高通量基因组学探索多种微生物的协同作用

• 批准号: 10417170
• 负责人: Richard J Lamont
• 金额: $ 55.56万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417170
• 关键词: Abscess; Actinobacillus actinomycetemcomitans; Adopted; Architecture; Bacteria; Biological; Biological Models; Communication; Communities; Complex; Development; Disease; Ecosystem; Genes; Genetic; Genomic approach; Genomics; Gingiva; Goals; Grant; Human; Image Analysis; Infection; Intervention; Investigation; Measures; Metabolic; Metagenomics; Microbe; Modeling; Molecular; Nature; Oral; Organism; Oxidative Stress; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Periodontal Diseases; Physiological; Porphyromonas gingivalis; Positioning Attribute; Process; Regulation; Research; Role; Sampling; Space Perception; Spatial Distribution; Streptococcus gordonii; Structure; Therapeutic; Time; Transcriptional Regulation; Translating; Virulence Factors; base; co-infection; design; dysbiosis; fitness; host microbiota; imaging study; in vivo; in vivo imaging; interspecies communication; metatranscriptomics; microbial; microbial community; mutant; novel; novel strategies; novel therapeutic intervention; oral infection; oral microbial community; oral plaque; pathogen; periodontopathogen; polymicrobial disease; prevent; public health relevance; quantitative imaging; spatial relationship; spatiotemporal; synergism; transcriptome; transcriptome sequencing; transposon sequencing

Polymicrobial infections are inherently more complex than mono-species infections, and this complexity has been a significant barrier to both a fuller appreciation of pathogenic mechanisms, and to the development of effective measures to control or prevent the disease. Periodontal diseases typify polymicrobial diseases, and are among the most common infections of humans. Although certain organisms, such as Porphyromonas gingivalis, are considered key pathogens, it is the polymicrobial community that initiates and drives the disease. In vivo imaging studies have shown that oral microbial communities are highly structured; however, little is known regarding the mechanisms that control spatial orientation within communities or the role of spatial structure in pathogenicity. Our ongoing studies have identified and quantified key spatial parameters in synergistic communities of the periodontal pathogen Aggregatibacter actinomycetemcomitans with S. gordonii. In this proposal, we will characterize the molecular basis and biological relevance of spatial parameters controlling the association of P. gingivalis with its community partners. In the first Aim, we will focus on the interaction between P. gingivalis and S. gordonii, a molecularly well-characterized process resulting in elevated pathogenicity of the dual species communities. We will determine the spatial parameters that define the dual species communities and their impact on pathogenicity. Further, through the use of specific mutants, we will assess the impact of known community virulence factors and communication mechanisms on spatial orientation. In the second Aim, we will use Tn-seq and RNA-seq genomic approaches to holistically assess the fitness determinants and transcriptome patterns which control spatial patterning in P. gingivalis and S. gordonii. We will prioritize potential contributors to metabolic synergy for further study of the relationship between spatial proximity and interspecies communication. In the third aim, we will explore Pg genetic pathways important for fitness during infection with a diverse set of co-infecting bacteria. The application of these focused and comprehensively based approaches will allow us to integrate key spatial parameters with molecular interspecies interactions in the context of community pathogenic potential. Successful completion of this project will provide fundamental information regarding the development and regulation of synergistic pathogenicity displayed by spatially defined polymicrobial communities which could ultimately be translated into therapeutic strategies designed to target the community-based pathogenesis that underlies periodontal disease.

多种微生物感染本质上比单一物种感染更复杂，并且这种复杂性 是更全面地了解致病机制和发展的重大障碍 采取有效措施控制或预防该病。牙周病是多种微生物疾病的典型代表，是 人类最常见的感染之一。尽管某些生物体，例如牙龈卟啉单胞菌， 被认为是关键病原体，正是多种微生物群落引发并驱动了疾病。体内 成像研究表明口腔微生物群落具有高度结构化；然而，人们知之甚少 关于控制社区内空间方向的机制或空间结构在社区中的作用 致病性。我们正在进行的研究已经确定并量化了协同作用中的关键空间参数 牙周病原体 Aggregatibacter actinomycetemcomitans 与 S. gordonii 的群落。在这个 建议，我们将描述控制空间参数的分子基础和生物学相关性 牙龈卟啉单胞菌与其社区合作伙伴的协会。在第一个目标中，我们将重点关注之间的交互 P. gingivalis 和 S. gordonii，一个分子上充分表征的过程，导致致病性升高 双物种群落。我们将确定定义双物种群落的空间参数 及其对致病性的影响。此外，通过使用特定突变体，我们将评估 已知的群落毒力因素和空间方向的沟通机制。在第二个目标中， 我们将使用 Tn-seq 和 RNA-seq 基因组方法来全面评估适应性决定因素和 控制 P. gingivalis 和 S. gordonii 空间模式的转录组模式。我们将优先考虑潜力 代谢协同作用的贡献者，以进一步研究空间​​邻近性和种间关系 沟通。在第三个目标中，我们将探索在感染期间对健康重要的 Pg 遗传途径。 一组不同的共感染细菌。这些针对性强、综合性方法的应用 将使我们能够将关键空间参数与分子种间相互作用结合起来 群落致病潜力。该项目的成功完成将提供基本信息 关于空间定义的协同致病性的发展和调节 多微生物群落最终可以转化为针对以下疾病的治疗策略 牙周病的基于社区的发病机制。