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：
9349336
负责人：
Gabriella Anne Szewczyk
金额：
$ 4.98万
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 2020-09-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9349336
关键词：
Address Adult Affect Alpha Cell 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 Family Gene Expression Gene Expression Regulation Genes Genetic Genetic Techniques Genetic Transcription Genome Goals Gram-Positive Bacteria Incidence Lead Mediating Microbial Biofilms Mind Minority Molecular Profiling Mono-S 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 differential expression experimental study gene function genome-wide improved insight intercellular communication lower income families mutant novel paralogous gene 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最普遍的慢性疾病世界人口3.4。经常与更严重的牙齿蛋白链球菌一起发现。12,18,19 许多导致突变链球菌的病毒因素已经得到很好的研究常规病毒基因表达的机制较少。 S. mutans的机制对开发的治疗方法至关重要的机制至关重要缓解龋齿。细胞到细胞通信机制称为Quorum Sensing（QS）21。我们实验室的先前工作已有证明RGG型QS途径调节生物膜形成和病毒性表达链球菌链球菌和遗传costics。utans26，35。我们已经确定了地址RGG 链球菌中的途径和我们的初步数据已经确定了每个RGG控制的假定病毒基因可以洞悉RGG QS电路的生物学功能。也可以通过与S. sobrinus的相互作用来影响。 S. mutans单独调节基因表达并在存在的机制中中心假设是，链球菌的病毒性基因表达是模块化的通过RGG介导的QS途径，尽管与S. sobrins相互作用。这项研究是（1）S。Mutans中RGG旁系同源物的描述调节功能和化学信号。表征链球菌和Sobinus相互作用的协同作用。在每个RGG调节中，我们将执行一系列表型实验，每个实验都利用了毒力我们的初步数据提出的特征是在RGG缺失突变体上。使用RNA-Seq的每个突变体的表达曲线来确定表型的基因基因网络观察并确定每个RGG的其他转录靶标。 Mutans的基因表达也将被评估。突变和s骨确定相互作用对基因表达的影响显示差异表达将是有助于种间相互作用的最高候选物这些途径将被生成并测试其贡献。研究将描述S. Mutans发病机理的关键方面，即地狱有助于改善策略预防和龋齿的知识也是实现长期的重要一步定义种类内和间隔的QS机制，该QS机制将模块化在S. mutans中，以及如何这些过程构成了促酶的发病机理。