Probing the role of heterogeneity in streptococcal interactions

项目摘要/摘要 链球菌是人类口腔中最丰富的微生物，大多数人都藏有多发性 物种，甚至经常是同一物种的多个菌株(1-6)。此外，虽然大多数种类的口腔 链球菌不是致病的，对选定菌株的研究表明，链球菌可以影响 牙龈卟啉单胞菌等口腔病原菌的物理定位和毒力因子表达， Aggregatibacter放线菌(AA)和核梭杆菌(2，3，7-11)。这些相互作用 影响疾病的进展和严重程度，以及对治疗的抵抗力(7、12-16)。然而， 这些相互作用也依赖于已知在不同属之间不同的特征，如细胞 表面结构和分泌的有机酸(17，18)。此外，转录的异质性导致了 亚群的存在，可以进一步改变链球菌的行为(19-23)。因此，虽然丰富的 链球菌属被认为是病原体行为的重要媒介，目前还不太清楚 链球菌和病原体的相互作用在该属的基因组和转录多样性中各不相同。在这 研究表明，最重要的假设是共生的基因组、表型和转录的异质性 链球菌改变与病原体的相互作用并影响感染。这项提议旨在扩大我们的 通过两个水平的多样性研究了解链球菌与病原体的相互作用：基因组和 转录的。首先，它建议系统地描述由分类多样性形成的相互作用 链球菌与病原体PG和AA在系统发育框架内(目标1)。这项工作将确定规模 链球菌属之间相互作用的差异，并可能识别新的调节功能 与这些病原体的相互作用。其次，这项提议将表征基因转录的异质性。 导致亚群的共生链球菌，并询问亚群如何影响和被影响 通过与口腔病原体的相互作用(目标2)。这一目标将极大地促进我们对 口腔共生链球菌的转录异质性及其在分类学上的变化和改变 由于环境的变化。此外，这两个目标都将考虑链球菌多样性和 微米级空间图案的相互作用。整体而言，拟议的研究将扩阔我们的 了解链球菌在口腔疾病中的作用。

PROJECT SUMMARY/ABSTRACT Streptococci are the most abundant microbes in the human oral cavity, with most people harboring multiple species, and often even multiple strains of the same species (1-6). Further, while most species of oral streptococci are not pathogenic, studies with selected strains have shown that streptococci can influence the physical location and the virulence factor expression of oral pathogens such as Porphyromonas gingivalis (Pg), Aggregatibacter actinomycetemcomitans (Aa), and Fusobacterium nucleatum (2, 3, 7-11). These interactions influence the progression and severity of disease, as well as its resistance to treatment (7, 12-16). However, these interactions also rely are governed by the traits that are known to vary across the genus, such as cell surface structures and secreted organic acids (17, 18). Further, transcriptional heterogeneity resulting in the existence of subpopulations, can further alter the behavior of streptococci (19-23). Thus, while the abundant streptococcal genus is thought of as an important mediator of pathogen behavior, it is not well understood how streptococcal-pathogen interactions vary across the genomic and transcriptomic diversity of the genus. In this study, the overarching hypothesis is that genomic, phenotypic, and transcriptional heterogeneity of commensal streptococci alters interactions with pathogens and impacts infections. This proposal aims to expand our understanding of streptococcal-pathogen interactions by investigating diversity at two levels: genomic and transcriptional. First, it proposes to systematically characterize the interactions formed by taxonomically diverse streptococci with the pathogens Pg and Aa in a phylogenomic framework (Aim 1). This work will identify the scale at which interactions vary across the streptococcal genus and potentially identify new functions that mediate interactions with these pathogens. Second, this proposal will characterize the transcriptional heterogeneity in commensal streptococci that result in subpopulations and ask how subpopulations influence, and are influenced by, interactions with oral pathogens (Aim 2). This aim will significantly advance our understanding of the role of transcriptional heterogeneity in oral commensal streptococci, how it varies taxonomically, and how it is altered by environmental changes. Further, both Aims will consider the interplay of streptococcal diversity and interactions on spatial patterning at the micron-level. Overall, the proposed research will broaden our understanding of the role of streptococci during oral disease.