Probing the role of heterogeneity in streptococcal interactions

探讨异质性在链球菌相互作用中的作用

• 批准号: 10284137
• 负责人: Gina Lewin
• 金额: $ 11.99万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284137
• 关键词: Abscess; Actinobacillus actinomycetemcomitans; Address; Animal Model; Area; Behavior; Cell surface; Cells; Communities; Complex; Development; Disease; Disease Outcome; Disease Progression; Fusobacterium nucleatum; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genomics; Genotype; Goals; Grant; Health; Health Promotion; Heterogeneity; Human; Hydrogen Peroxide; In Vitro; Infection; Laboratories; Location; Measures; Mediating; Mediator of activation protein; Microbe; Microscopy; Modeling; Mouth Diseases; Mus; Oral; Oral cavity; Pattern; Periodontitis; Phenotype; Physiology; Population; Porphyromonas gingivalis; Production; Research; Research Personnel; Resistance; Role; Severity of illness; Shapes; Spatial Distribution; Streptococcus; Streptococcus adhesin; Structure; Taxonomy; Testing; Training; Variant; Virulence Factors; Work; base; commensal bacteria; environmental change; gain of function; improved; innovation; loss of function; member; mutant; novel strategies; oral behavior; oral commensal; oral microbial community; oral pathogen; oral streptococci; organic acid; pathogen; receptor; single-cell RNA sequencing; small molecule; trait; transcriptomics

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.

项目概要/摘要 链球菌是人类口腔中最丰富的微生物，大多数人都携带多种链球菌。 物种，通常甚至是同一物种的多个菌株 (1-6)。此外，虽然大多数物种的口腔 链球菌不具有致病性，对选定菌株的研究表明，链球菌可以影响 口腔病原体如牙龈卟啉单胞菌（Pg）的物理位置和毒力因子表达， 伴放线聚集杆菌 (Aa) 和具核梭杆菌 (2, 3, 7-11)。这些互动 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存在差异的特征，例如细胞 表面结构和分泌的有机酸 (17, 18)。此外，转录异质性导致 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 链球菌属被认为是病原体行为的重要介质，但目前尚不清楚如何 链球菌-病原体相互作用因该属的基因组和转录组多样性而异。在这个 研究的首要假设是共生体的基因组、表型和转录异质性 链球菌改变与病原体的相互作用并影响感染。该提案旨在扩大我们的 通过研究两个层面的多样性来了解链球菌-病原体相互作用：基因组和 转录的。首先，它建议系统地描述分类多样性形成的相互作用 系统发育框架中具有病原体 Pg 和 Aa 的链球菌（目标 1）。这项工作将确定规模 链球菌属之间的相互作用各不相同，并可能识别出介导的新功能 与这些病原体的相互作用。其次，该提案将描述转录异质性 共生链球菌产生亚群，并询问亚群如何影响以及被影响 与口腔病原体的相互作用（目标 2）。这一目标将极大地增进我们对 口腔共生链球菌的转录异质性，它在分类学上如何变化以及如何改变 通过环境变化。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。总体而言，拟议的研究将拓宽我们的研究范围 了解链球菌在口腔疾病中的作用。