Streptococcus mutans is considered the principal etiological agent of human dental caries. The ability of the organism to survive a variety of harmful or stressful conditions and to emerge as numerically significant member of stable oral biofilm communities are essential elements for the persistence and cariogenicity of S. mutans. Such abilities are critical to understand how this organism colonizes and persists in specific niches, and are likely to interconnect with sophisticated adaptation mechanisms that allow the organism to maintain homeostasis within the dynamic oral microflora. This important aspect of S. mutans physiology will be pursued in this proposal by studying the homologous cidAB and lrgAB operons, recently identified as being highly balanced and coordinated during S. mutans growth in oxygen, as well as shown to play a significant role in a variety of key S. mutans virulence traits, including autolysis, biofilm formation, oxidative and heat stress, and genetic competence. More importantly, the cid and lrg operons were predicted to be analogous to bacteriophage-encoded holin/antiholin proteins (suggested to control the activity of bacteriophage-mediated cell death and lysis). The goals of this proposal are 1) to decipher the reciprocal regulatory circuits of regulatory feedback between the cid and lrg genes, 2) to identify and characterize the Cid/Lrg-mediated cellular and molecular mechanisms in S. mutans, and 3) to evaluate contribution of Cid and Lrg to the competitive fitness of S. mutans in-vitro and in-vivo. These objectives will advance our understanding of how S. mutans persists in biofilms that harbor a highly complex population of differentiated cells and dynamic metabolic processes, and represent a new avenue of bacterial programmed cell death research that will further fundamental knowledge relevant to other oral streptococci and Gram-positive organisms. Furthermore, establishing a link between biofilm development and cell death/lysis will provide another valuable insight into inhibition of the initiation or progression of dental caries and possibilities for improved therapy and disease control.

Public Health Relevance

Despite the implementation of public health measures (water fluoridation, school-based dental sealant programs) aimed at its eradication, dental caries remains globally-prevalent as the most common chronic disease among children, and is also common among adolescent and adults. Streptococcus mutans has been considered the primary causative agent of dental caries, and like other oral streptococcal species, can also cause infective endocarditis in at-risk patients. Therefore, research that contributes to our understanding of how this pathogen is able to survive and withstand oxidative stress in the oral cavity, and how these stress pathways affect multi-species plaque biofilm development, will facilitate the development of novel preventative and/or treatment strategies for both of these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE025237-03
Application #
9433638
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Florida
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Ahn, Sang-Joon; Gu, Tongjun; Koh, Jin et al. (2017) Remodeling of the Streptococcus mutans proteome in response to LrgAB and external stresses. Sci Rep 7:14063
Rice, Kelly C; Turner, Matthew E; Carney, O'neshia V et al. (2017) Modification of the Streptococcus mutans transcriptome by LrgAB and environmental stressors. Microb Genom 3:e000104
Ahn, Sang-Joon; Rice, Kelly C (2016) Understanding the Streptococcus mutans Cid/Lrg System through CidB Function. Appl Environ Microbiol 82:6189-6203