Despite substantial progress in prevention and treatment, dental caries, commonly known as tooth decay or cavities, remains one of the most common and costly infectious diseases worldwide. According to the CDC, associated health care costs more than 80 billion dollars annually, and the rates of childhood caries in the United States are rising. Novel, comprehensive strategies are needed to effectively combat caries pathogenesis. Cariogenic bacteria form tenacious biofilms on the surface of teeth known as dental plaque. Supported by R01 DE019452, we have over the past five years generated seminal evidence that biofilm regulatory protein BrpA, a member of the LytR-CpsA-Psr family of cell envelope associated proteins, plays a critical role in regulation of cell envelope biogenesis and biofilm formation by Streptococcus mutans. The overall goals of this continuation are to elucidate how BrpA regulates S. mutans stress tolerance response and biofilm formation, traits critical to pathogenicity of this key etiological agent of human dental caries, and to explore the potential of targeting BrpA in strategy against S. mutans and dental caries. In this study, we will use an integrative approach that includes modern molecular and biochemical techniques, such as yeast two-hybrid system, and traditional animal caries model (i) to elucidate the mechanisms that govern the expression of this important streptococcal protein, (ii) to identify protein(s) tha interact with BrpA and uncover how BrpA regulates S. mutans pathophysiology, and (iii) to determine the effects of disrupting BrpA on the ability of S. mutans to colonize the tooth surface and cause carious diseases. Elucidation of cis- and trans-acting factors involved in regulation of BrpA expression and uncovering of proteins interactive with BrpA and their roles in BrpA-mediated functions will constitute a major breakthrough in our understanding of not only just BrpA, but also the LCP family of proteins in regulation of cellular biology in S. mutans and other Gram-positive bacteria. Such findings are expected to facilitate the formulation/development of novel comprehensive strategies against tooth decay and potentially other infections caused by Gram-positive bacteria.

Public Health Relevance

This study investigates how Streptococcus mutans modulates its production of BrpA protein in response to various environmental perturbations and how BrpA regulates S. mutans' abilities to cope with various environmental insults, to persist and accumulate on the tooth surface, and to cause carious lesions. Information derived from this study will facilitate the design of therapeutic and preventative strategies to combat human dental caries.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE019452-05
Application #
8888740
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
2008-12-01
Project End
2020-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
5
Fiscal Year
2015
Total Cost
$465,131
Indirect Cost
$113,004
Name
Louisiana State Univ Hsc New Orleans
Department
Dentistry
Type
Schools of Dentistry
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
De, Arpan; Jorgensen, Ashton N; Beatty, Wandy L et al. (2018) Deficiency of MecA in Streptococcus mutans Causes Major Defects in Cell Envelope Biogenesis, Cell Division, and Biofilm Formation. Front Microbiol 9:2130
Wen, Zezhang T; Scott-Anne, Kathleen; Liao, Sumei et al. (2018) Deficiency of BrpA in Streptococcus mutans reduces virulence in rat caries model. Mol Oral Microbiol 33:353-363
Lee, Janelle; Townsend, Janice A; Thompson, Tatyana et al. (2018) Analysis of the Cariogenic Potential of Various Almond Milk Beverages using a Streptococcus mutans Biofilm Model in vitro. Caries Res 52:51-57
Garcia, S S; Blackledge, M S; Michalek, S et al. (2017) Targeting of Streptococcus mutans Biofilms by a Novel Small Molecule Prevents Dental Caries and Preserves the Oral Microbiome. J Dent Res 96:807-814
De, Arpan; Liao, Sumei; Bitoun, Jacob P et al. (2017) Deficiency of RgpG Causes Major Defects in Cell Division and Biofilm Formation, and Deficiency of LytR-CpsA-Psr Family Proteins Leads to Accumulation of Cell Wall Antigens in Culture Medium by Streptococcus mutans. Appl Environ Microbiol 83:
Besingi, Richard N; Wenderska, Iwona B; Senadheera, Dilani B et al. (2017) Functional amyloids in Streptococcus mutans, their use as targets of biofilm inhibition and initial characterization of SMU_63c. Microbiology 163:488-501
Liao, S; De, A; Thompson, T et al. (2017) Expression of BrpA in Streptococcus mutans is regulated by FNR-box mediated repression. Mol Oral Microbiol 32:517-525
Wen, Zezhang T; Liao, Sumei; Bitoun, Jacob P et al. (2017) Streptococcus mutans Displays Altered Stress Responses While Enhancing Biofilm Formation by Lactobacillus casei in Mixed-Species Consortium. Front Cell Infect Microbiol 7:524
Bitoun, J P; Wen, Z T (2016) Transcription factor Rex in regulation of pathophysiology in oral pathogens. Mol Oral Microbiol 31:115-24
Wen, Zezhang T; Bitoun, Jacob P; Liao, Sumei (2015) PBP1a-deficiency causes major defects in cell division, growth and biofilm formation by Streptococcus mutans. PLoS One 10:e0124319

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