DETERMINATION OF THE ROLE OF Smu.833 IN THE FITNESS AND VIRULENCE OF CARIOGENIC STREPTOCOCCUS MUTANS

测定 Smu.833 在致龋性变形链球菌的适应性和毒力中的作用

• 批准号: 9049913
• 负责人: Katherine L. Rainey
• 金额: $ 4.39万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9049913
• 关键词: Adherence; Alabama; Bacteria; Bacterial Adhesins; Binding; Binding Proteins; Biological Assay; Caries prevention; Cell Fraction; Child; Collaborations; Collagen; Communicable Diseases; Complement; Complex; Data; Dental Enamel; Dental caries; Diet; Dietary Sucrose; Dietary Sugars; Disease; Eating; Elderly; Environment; Enzymes; Gel; Genes; Genetic; Glucans; Glucose; Glucosyltransferases; Goals; Health; Homologous Gene; Hydrogen Peroxide; Impairment; In Vitro; Infective endocarditis; Intake; Lactic acid; Length; Mass Spectrum Analysis; Metabolism; Microbial Biofilms; Modeling; Modification; Nutritional; Oral cavity; Oxidative Stress; Pain; Parents; Pathway interactions; Phenotype; Play; Population; Prevalence; Production; Proteins; Proteomics; Rattus; Regulation; Research; Role; Science; Serotyping; Streptococcus mutans; Surface; Testing; Therapeutic Uses; Universities; Virulence; Virulence Factors; commensal microbes; demineralization; effective therapy; extracellular; fitness; genetic regulatory protein; genome-wide; glucosyltransferase B; glycosylation; glycosyltransferase; in vivo Model; interest; killings; mutant; new therapeutic target; novel; oral commensal; oral pathogen; pathogenic bacteria; polymerization; protein profiling; protein protein interaction; public health relevance; targeted treatment; therapeutic target; tooth surface

 DESCRIPTION (provided by applicant): Dental caries, more commonly known as tooth decay, is the most common infectious disease worldwide and is increasing in prevalence among young children despite advancements in caries research. Untreated cavities can cause severe pain and impairment of eating, leading to reduced nutritional intake and diet-related ill health especially for children and the elderly. The main etiological agent of dental caries is Streptococcus mutans which can readily form a biofilm on the surface of teeth and produce lactic acid through the metabolism of dietary sugars which is largely responsible for the demineralization and subsequent destruction of tooth enamel. In addition, S. mutans synthesizes extracellular glucosyltransferases (Gtfs) capable of breaking apart dietary sucrose and polymerizing the glucose subunits into the sticky glucan matrix of the biofilm, imperative for the formation of robust, three-dimensional biofilms. Currently used caries therapies are not species-specific and kill pathogenic species as well as commensal species which are protective against the formation of pathogenic biofilms. There are a number of proteins in S. mutans whose function remains unknown but which could present new targets for S. mutans specific anti-caries treatment. One such protein is a conserved, putative glycosyltransferase encoded by the gene smu.833 in S. mutans strain UA159. A homologue of Smu.833 in a different serotype of S. mutans, has been shown to glycosylate an important surface collagen binding protein important for bacterial colonization in infective endocarditis. Thus, this protein makes a good candidate to be studied and analyzed for its potential as a target for caries therapies. In order o characterize this protein in S. mutans, we created a deletion mutant and assayed for phenotypic changes in bacterial fitness and virulence. Initial studies revealed decreased levels of Gtfs and subsequent glucan matrix formation within the mutant, as well as additional intriguing phenotypes including increased bacterial chain length and aggregation, increased sensitivity to oxidative stress, and increased levels of biofilm regulatory protein. The results obtained thus far have led to the hypothesis that Smu.833 is required both for Gtf glycosylation and stability and for an additional role in S. mutans which more globally effects bacterial fitness and virulence. To test this hypothesis, we propose three specific aims: Aim 1: Determine the role of Smu.833 in Gtf expression; Aim 2: Determine the global role Smu.833 plays in bacterial fitness and virulence ; Aim 3: Determine the effect of Smu.833 on bacterial competitiveness. Elucidating the role of Smu.833 in S. mutans will help unravel the complex interactions that govern the fitness and virulence of this bacterium. Furthermore, results from this application may present a new species-specific target for therapeutics used in the prevention of dental caries, a costly and painful disease which effects the vast majority of the world's population.