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Virulence Outcomes Pertaining to Streptococcus mutans’ Social Interactions

与变形链球菌社会互动相关的毒力结果

基本信息

批准号：
10057352
负责人：
Gabriella Anne Szewczyk
金额：
$ 5.13万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-16 至 2021-05-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057352
关键词：
Address Adult Affect Attention Attenuated Bacteria Behavior Biological Process Cell Communication Cells Chemicals Child Chronic Chronic Disease Clinical Communicable Diseases Competence DNA Data Dental Dental Care Dental Plaque Dental caries Development Diet Disease Environmental Exposure Equilibrium Etiology Expression Profiling Family Financial Hardship Gene Expression Gene Expression Profiling Gene Expression Regulation Genes Genetic Genetic Techniques Genetic Transcription Genome Goals Gram-Positive Bacteria Healthcare Incidence Lead Mediating Microbial Biofilms Mind Minority Odontogenesis Oral health Outcome Pathogenesis Pathogenicity Pathway interactions Peptides Phenotype Pheromone Play Population Prevention strategy Preventive therapy Process Regulation Regulatory Pathway Regulon Reporting Research Reverse Transcriptase Polymerase Chain Reaction Role Series Signal Transduction Social Interaction Streptococcus Streptococcus mutans Streptococcus pyogenes Streptococcus sobrinus System Testing Therapeutic Toxin Virulence Virulence Factors Work base burden of illness cariogenic bacteria combat dental biofilm differential expression experimental study gene function genome-wide improved insight intercellular communication lower income families mutant novel paralogous gene polymicrobial biofilm quorum sensing receptor social synergism trait transcriptome transcriptome sequencing transcriptomics uptake

项目摘要

PROJECT SUMMARY Dental caries is the most prevalent chronic disease in both children and adults, affecting 80–90% of the world population3.4. The bacterium, Streptococcus mutans, is the primary causative agent of this disease and is frequently found together with Streptococcus sobrinus in situations of more severe dental caries12,18,19. While many of the virulence factors contributing to the cariogenicty of S. mutans have been well studied, the mechanisms that regulate virulence gene expression has received less attention. Understanding the mechanisms by which S. mutans regulates its virulence are critical for developing therapeutic approaches to mitigate dental caries. Many bacteria, including streptococci, are known to regulate gene expression through a cell-to-cell communication mechanism called quorum sensing (QS) 21. Previous work by our lab has demonstrated that Rgg-type QS pathways regulate biofilm formation and virulence expression in Streptococcus pyogenes and genetic competence in S. mutans 26, 35. We have identified additional Rgg pathways in S. mutans and our preliminary data has identified putative virulence genes controlled by each Rgg thereby providing insight on the biological function of Rgg QS circuits. Moreover, the virulence of S. mutans may also be influenced through interactions with S. sobrinus. The current proposal will explore the mechanisms by which S. mutans regulates gene expression alone and in the presence of S. sobrinus. The central hypothesis of this proposal is that virulence gene expression by S. mutans is modulated through Rgg-mediated QS pathways and through its interaction with S. sobrinus. The specific aims of this research are (1) Describe regulatory function and chemical signaling for Rgg paralogs in S. mutans. (2) Characterize the synergistic effects of S. mutans and S. sobrinus interaction. To elucidate the functional roles of each Rgg regulon, we will perform a series of phenotypic experiments, each of which exploits a virulence trait suggested by our preliminary data, on rgg deletion mutants. We will then analyze the genome-wide expression profile of each mutant using RNA-seq to determine gene networks underpinning the phenotypes observed and to identify additional transcriptional targets of each Rgg. The influence of S. sobrinus on S. mutans’ gene expression will also be assessed. We will preform RNA-seq on dual-species biofilms of S. mutans and S. sobrinus to determine the influence of this interaction on gene expression. Genetic pathways showing differential expression will be top candidates that contribute to interspecies interaction, and mutants of these pathways will be generated and tested for their contribution to virulence. It is anticipated that this research will delineate critical aspects of S. mutans pathogenesis that will help improve strategies of prevention and treatment of dental caries. This research is also an important step in achieving the long-term goal of defining the intra- and interspecies QS mechanisms that modulate virulence in S. mutans, and how these processes contribute to disease pathogenesis.

项目摘要龋齿是儿童和成人中最常见的慢性疾病，影响 80-90% 的儿童世界人口3.4。变形链球菌是这种疾病的主要病原体，并且是在较严重的龋齿情况下，经常与 Sobrinus 链球菌一起发现12,18,19。尽管许多导致变形链球菌致龋性的毒力因素已得到充分研究，调节毒力基因表达的机制受到的关注较少。了解变形链球菌调节其毒力的机制对于开发治疗方法至关重要减轻龋齿。已知许多细菌，包括链球菌，可以通过细胞间的通讯机制称为群体感应 (QS) 21. 我们实验室之前的工作有证明 Rgg 型 QS 途径调节生物膜的形成和毒力表达化脓性链球菌和变形链球菌的遗传能力 26、35。我们已经鉴定出额外的 Rgg 变异链球菌中的途径，我们的初步数据已经确定了由每个 Rgg 控制的推定毒力基因从而提供对 Rgg QS 回路的生物学功能的见解。此外，变形链球菌的毒力也可能通过与 S. sobrinus 的相互作用而受到影响。目前的提案将探讨 S. mutans 单独调节基因表达的机制以及在 S. sobrinus 存在的情况下调节基因表达的机制。这该提案的中心假设是变形链球菌的毒力基因表达受到调节通过 Rgg 介导的 QS 途径及其与 S. sobrinus 的相互作用。具体目标这项研究是 (1) 描述变形链球菌中 Rgg 旁系同源物的调节功能和化学信号传导。 (2) 表征 S. mutans 和 S. sobrinus 相互作用的协同效应。阐明职能角色对于每个 Rgg 调节子，我们将进行一系列表型实验，每个实验都利用毒力我们的初步数据表明，关于 rgg 缺失突变体的特征。然后我们将分析全基因组使用 RNA-seq 确定每个突变体的表达谱以确定支撑表型的基因网络观察并确定每个 Rgg 的其他转录目标。 S. sobrinus 对 S. sobrinus 的影响。突变体的基因表达也将被评估。我们将对链球菌的双物种生物膜进行 RNA 测序。 mutans 和 S. sobrinus 以确定这种相互作用对基因表达的影响。遗传途径显示差异表达将是有助于种间相互作用的最佳候选者，并且突变体这些途径将被生成并测试其对毒力的贡献。预计这研究将描述变形链球菌发病机制的关键方面，这将有助于改进治疗策略预防和治疗龋齿。这项研究也是实现长期目标的重要一步定义调节变形链球菌毒力的种内和种间 QS 机制的目标，以及如何这些过程有助于疾病的发病机制。