Probing Polymicrobial Synergy Using High Throughput Genomics

多微生物感染本质上比单物种感染更复杂，并且这种复杂性 一直是一个重大的障碍，既全面了解致病机制，并发展 采取有效措施控制或预防疾病。牙周病是多种微生物疾病的典型， 是人类最常见的感染之一虽然某些生物，如牙龈卟啉单胞菌， 被认为是关键的病原体，它是启动和驱动疾病的多微生物群落。体内 影像学研究表明，口腔微生物群落是高度结构化的;然而， 关于控制社区内空间方向的机制或空间结构在社区内的作用， 致病性我们正在进行的研究已经确定和量化了协同作用的关键空间参数。 牙周致病菌伴放线菌聚集杆菌与S. gordonii。在这 建议，我们将表征控制的空间参数的分子基础和生物相关性， 牙龈卟啉单胞菌与其社区合作伙伴的关系。在第一个目标中，我们将重点关注 P. gingivalis和S. gordonii，一个分子特征良好的过程，导致致病性的提高， 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，通过使用特定的突变体，我们将评估 已知的群落毒力因子和空间定向的通讯机制。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， 转录组模式控制牙龈卟啉单胞菌和S. gordonii。我们将优先考虑潜在的 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 通信在第三个目标中，我们将探索在感染期间对适应性重要的Pg遗传途径。 一组不同的共感染细菌这些重点突出、基础全面的方法的应用 将使我们能够整合关键的空间参数与分子物种间的相互作用， 社区致病潜力该项目的成功完成将提供基本信息 关于空间上定义的病毒所显示的协同致病性的发展和调节， 多微生物群落，最终可以转化为治疗策略，旨在针对 牙周病的病因是什么？

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.