The current knowledge implicating Streptococcus mutans as a major cariogenic bacterium is mainly based on the correlation of human caries rates vs levels of S. mutans in oral cavities or the induction of dental caries via inoculation of . mutans in various animal models. This evidence is substantial but not conclusive as S. mutans is just one of the hundreds of species in oral cavity. Traditional approaches focused on single and dual species interactions are valuable but simply cannot provide the definitive answer on whether or not S. mutans is the keystone cariogenic pathogen responsible for maintaining or shifting the cariogenicity of the oral microbial community towards the disease state. In the previous cycle, we developed state-of-the-art technologies (such as metagenomic-guided community model development, combined SIP with real-time NMR metabolomics, bacterial surface-displayed pH-sensitive green fluorescent protein) that enabled simultaneous detection of oral bacteria (including uncultivable bacteria) and their acidic metabolites within multi-specie dental plaque in situ and in real-time. By connecting S. mutans' pheromone CSP to an antimicrobial peptide, we created a targeted antimicrobial peptide C16G2 with high specificity and sensitivity against S. mutans. We demonstrated its killing ability via selective membrane disruption and validated its safety. These recently developed tools provided new biological insights connecting key bacteria and functions to the cariogenic process in multi-species settings. The interesting and intriguing results derived from these studies provided a strong indication that S. mutans, with an ability to coordinate its three key cariogenic virulence factors (glucan production, acidogenicity and acidurity), can greatly enhance its fitness against acid stress, which could be the reason for its ability to disrupt the normal homeostasis of the oral microbial community and drive conditions towards a disease state. Based on our exciting preliminary data, we developed the following two working hypotheses to address these questions: 1) S. mutans has unique capacities to integrate its three major virulence factors (glucan production, acidogenicity and acidurity) to enhance its fitness in low pH than other oral species, which may be responsible for maintaining the cariogenic activity of the oral microbial community; 2) The targeted removal of S. mutans would allow the reestablishment of the healthy oral microbial community. This application aims to test our hypothesis using a combined genomic, genetic, biochemical and physiological study under both in vitro and in vivo conditions. The success of this study would greatly expand our knowledge of oral microbial pathogenesis by uncovering integrated virulence functions that facilitate survival and persistence of S. mutans. It will also have a direct and immediate impact on the clinical management of dental caries through our new therapeutic interventions.

Public Health Relevance

Streptococcus mutans is considered the major harmful bacterium causing tooth decay in human. Our research is focused on using newly developed technologies and novel tools to study and better understand why this particular bacterium, among hundreds of other oral bacteria, plays such a significant role in causing tooth decay.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE020102-06
Application #
9186534
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
2010-05-01
Project End
2020-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
He, X; Li, F; Bor, B et al. (2018) Human tRNA-Derived Small RNAs Modulate Host-Oral Microbial Interactions. J Dent Res 97:1236-1243
Baker, J L; Lindsay, E L; Faustoferri, R C et al. (2018) Characterization of the Trehalose Utilization Operon in Streptococcus mutans Reveals that the TreR Transcriptional Regulator Is Involved in Stress Response Pathways and Toxin Production. J Bacteriol 200:
Yang, Yin; Reipa, Vytas; Liu, Guo et al. (2018) pH-Sensitive Compounds for Selective Inhibition of Acid-Producing Bacteria. ACS Appl Mater Interfaces 10:8566-8573
Bedree, Joseph K; Bor, Batbileg; Cen, Lujia et al. (2018) Quorum Sensing Modulates the Epibiotic-Parasitic Relationship Between Actinomyces odontolyticus and Its Saccharibacteria epibiont, a Nanosynbacter lyticus Strain, TM7x. Front Microbiol 9:2049
Xu, He; Tian, Jing; Hao, Wenjing et al. (2018) Oral Microbiome Shifts From Caries-Free to Caries-Affected Status in 3-Year-Old Chinese Children: A Longitudinal Study. Front Microbiol 9:2009
Bor, Batbileg; McLean, Jeffrey S; Foster, Kevin R et al. (2018) Rapid evolution of decreased host susceptibility drives a stable relationship between ultrasmall parasite TM7x and its bacterial host. Proc Natl Acad Sci U S A 115:12277-12282
Shen, Mengyu; Yang, Yuhui; Shen, Wei et al. (2018) A Linear Plasmid-Like Prophage of Actinomyces odontolyticus Promotes Biofilm Assembly. Appl Environ Microbiol 84:
Edlund, Anna; Garg, Neha; Mohimani, Hosein et al. (2017) Metabolic Fingerprints from the Human Oral Microbiome Reveal a Vast Knowledge Gap of Secreted Small Peptidic Molecules. mSystems 2:
Guo, Lihong; Shokeen, Bhumika; He, Xuesong et al. (2017) Streptococcus mutans SpaP binds to RadD of Fusobacterium nucleatum ssp. polymorphum. Mol Oral Microbiol 32:355-364
Hanson-Drury, Sesha; To, Thao T; Liu, Quanhui et al. (2017) Draft Genome Sequence ofTannerella forsythiaClinical Isolate 9610. Genome Announc 5:

Showing the most recent 10 out of 54 publications