Ecological Consequences of Cell-Cell Signaling on Interbacterial Competition

细胞间信号传导对细菌间竞争的生态影响

• 批准号: 9683262
• 负责人: Justin Ray Kaspar
• 金额: $ 5.98万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2019-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9683262
• 关键词: Adult; Age; Applications Grants; Architecture; Bacteria; Carbohydrates; Cells; Child; Childhood; Chlorhexidine; Chronic; Chronic Disease; Competence; DNA; Dental Plaque; Dental caries; Developed Countries; Development; Disease; Ecology; Environment; Etiology; Evolution; Fluorides; Fostering; Foundations; Gene Expression; Genes; Genetic; Genetic Materials; Genetic Transcription; Genome; Growth; Health; Health Expenditures; Homeostasis; Horizontal Gene Transfer; Human; Intake; Lesion; Libraries; Metabolic; Microbial Biofilms; Modeling; Monitor; Mus; Natural Products; Nucleotides; Nutrient; Oral; Oral cavity; Oral health; Organism; Pathway interactions; Peptides; Phylogenetic Analysis; Pit and Fissure Sealants; Play; Population; Prevalence; Prevention strategy; Probiotics; Quality of life; Recovery; Rodent Model; Role; Seeds; Sigma Factor; Source; Streptococcus; Streptococcus mutans; Structure; System; Testing; Time; Tooth Demineralization; Virulence; Water Supply; World Health Organization; anticaries; bacteriocin; biological adaptation to stress; cariogenic bacteria; combat; commensal bacteria; dental agent; design; environmental stressor; extracellular; fitness; in vivo; inhibitor/antagonist; inorganic phosphate; intercellular communication; interest; member; microbial; microorganism; mouse model; neglect; novel; novel therapeutics; oral bacteria; oral biofilm; oral commensal; oral infection; organic acid; pathogen; pressure; quorum sensing; repaired; response; stress tolerance; sugar; tooth surface; uptake

PROJECT SUMMARY Environmental fluctuations in the human oral cavity favor an increase in the number of cariogenic bacteria, including Streptococcus mutans, one of the etiological agent of human dental caries. Dental caries is the most common chronic disease in children, can greatly impact quality of life, and represents 5-10% of healthcare expenditures in industrialized nations. One attractive strategy towards the growth inhibition of cariogenic bacteria is an oral bacteria probiotic approach that seeds oral biofilms with beneficial commensals that can moderate plaque acidification and interfere with the colonization and virulence of caries pathogens such as S. mutans. Thus, a better understanding of the mechanisms by which health-associated bacteria antagonize and compete with cariogenic bacteria is needed. The virulence of S. mutans resides in three core attributes: its ability to form biofilms on the tooth surface, to produce large quantities of organic acids from a wide range of carbohydrates, and its ability to tolerate environmental stressors. Of interest, a very strong correlation exists between stress tolerance, biofilm formation and natural genetic competence [or the ability to uptake external DNA from the environment]. Recently, our group developed a Tn-seq library in S. mutans for discovering regions of the genome that are required for the survival of bacteria in different environments. Interestingly, when the library was input into an in vivo rodent model of oral infection, genes involved in genetic competence (comR, comX) showed an enhancement in recovery suggesting that their deletion led to an increase in fitness. This contrasts with the fact that many of the competence genes are highly conserved across human isolates of S. mutans signifying an evolutionary pressure to keep the competence pathway intact. One hypothesis is that the mouse caries model may not fully recapitulate the selective pressures found in the human host; the competence genes may play an important role in competition with commensal bacteria that is either suppressed or not present in the mouse model used. Therefore, we purpose two critical aims of this grant application to evaluate the impact of competence development in the ecology and development of oral biofilms. In Aim 1, we will test a library of novel streptococcal species that were isolated from dental plaque of subjects of known caries status that display a wide range of antagonistic capabilities towards S. mutans and determine if the S. mutans cell-cell signaling response is altered when these strains are cultured together. In Aim 2, we will elucidate how modulation of S. mutans cell-cell signaling either fosters or inhibits the establishment and outgrowth of S. mutans by monitoring the fitness of mixed-species biofilm populations, changes in biofilm architecture, and alterations in the spatial arrangement between competing strains at selected time points. Together, the results found here will establish a new foundation for the design and discovery of new and novel anti-caries therapies, and allow us to determine the ecological consequences of selective inhibition in oral biofilm populations.

项目摘要 人类口腔中的环境波动有利于致龋细菌数量的增加， 包括变形链球菌（Streptococcus mutans），其是人类龋齿的病原体之一。龋齿是最 儿童常见的慢性疾病，可极大地影响生活质量，占医疗保健的5-10% 工业化国家的支出。一个有吸引力的策略对生长抑制致龋 bacteria是一种口腔细菌益生菌的方法， 适度的菌斑酸化和干扰龋齿病原体如S. 变异人因此，更好地了解健康相关细菌拮抗和 需要与致龋细菌竞争。对S. mutans存在于三个核心属性中： 在牙齿表面形成生物膜的能力，从各种各样的有机酸中产生大量的有机酸， 碳水化合物，以及其耐受环境压力的能力。有趣的是， 胁迫耐受性、生物膜形成和天然遗传能力[或吸收外部环境的能力]之间的关系 环境中的DNA）。最近，我们的小组在S.变异体的发现 细菌在不同环境中生存所需的基因组区域。有趣的是， 当将该文库输入口腔感染的体内啮齿动物模型时， (comR，comX）显示出恢复的增强，表明它们的缺失导致适应性的增加。 这与许多感受态基因在人类分离株中高度保守的事实形成对比， S.变异体意味着保持能力通路完整的进化压力。一种假设是， 小鼠龋齿模型可能无法完全概括人类宿主中发现的选择压力; 感受态基因可能在与细菌的竞争中起重要作用， 抑制或不存在于所使用的小鼠模型中。因此，我们的目的是两个关键的目标，这一赠款 应用评价能力发展对口腔生物膜的生态学和发育的影响。 在目标1中，我们将测试从受试者牙菌斑中分离的新型链球菌物种的文库 已知的龋齿状态，显示出广泛的拮抗能力，对S。变形和确定 如果S.当这些菌株一起培养时，变形菌细胞-细胞信号传导反应改变。在目标2中， 将阐明S.变形细胞-细胞信号传导促进或抑制了 S.通过监测混合物种生物膜种群的适合度，生物膜的变化， 结构，以及在选定的时间点竞争菌株之间的空间排列的改变。 总之，这里发现的结果将为设计和发现新的和新颖的 抗龋治疗，并使我们能够确定口腔选择性抑制的生态后果， 生物膜种群。