The proposed research aims to investigate the molecular mechanisms used by the irvR/A regulatory system of Streptococcus mutans to control numerous accessory gene pathways in response to environmental stress. Our previous studies demonstrated that the central regulator of this system irvA is a riboregulatory mRNA. Its principal regulatory function is mediated through seed pairing with irvA mRNA, rather than through the function of its encoded protein. Such regulatory control is a new paradigm for the function of mRNAs. In this project, we are interested to determine the mechanisms used by S. mutans to modulate irvA expression, the role of irvA as a pleiotropic riboregulatory mRNA, and the ability of irvA to exploit the regulatory ribonuclease RNase J2 for the posttranscriptional control of gene expression. The goals of the project will be completed in three Aims. 1) To determine the mechanism controlling irvA expression, we will characterize the protein-protein interactions that modulate the stability and function of the proximal regulator of irvA gene expression, IrvR. This mechanism will be tested for its role in modulating biofilm integrity during environmental stress. 2) To understand the role of irvA as a pleiotropic riboregulatory mRNA, we will identify the overlapping geneset between the irvA regulon and a newly identified RNA chaperone required for irvA riboregulation. These genes will be tested for irvA- and chaperone-dependent regulation of target mRNA stability and seed pairing. 3) To investigate the ability of irvA to exploit RNase J2 for the control of gene expression, we will test irvA and RNA chaperone for their ability to modulate RNase J2 degradation of irvA target mRNAs via seed pairing. We will also determine the recognition elements in RNA that specify cleavage by RNase J2. The proposed studies will provide some of the first mechanistic insights into the posttranscriptional regulatory mechanisms used by oral bacteria and will demonstrate how key pathways are regulated in response to environmental stress. This will hopefully add an important layer to our understanding of S. mutans ability to influence oral ecology.

Public Health Relevance

Dental caries is one of the most common diseases worldwide and Streptococcus mutans is among the most frequently detected organisms in caries lesions. This study aims to understand S. mutans role in the pathogenesis of caries by focusing upon its ability to regulate virulence in response to environmental stress.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE018893-08
Application #
9185966
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
2008-04-01
Project End
2020-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Merritt, Justin; Senpuku, Hidenobu; Kreth, Jens (2016) Let there be bioluminescence: development of a biophotonic imaging platform for in situ analyses of oral biofilms in animal models. Environ Microbiol 18:174-90
Itzek, A; Chen, Z; Merritt, J et al. (2016) Effect of salivary agglutination on oral streptococcal clearance by human polymorphonuclear neutrophil granulocytes. Mol Oral Microbiol :
Esteban Florez, Fernando Luis; Hiers, Rochelle Denise; Smart, Kristin et al. (2016) Real-time assessment of Streptococcus mutans biofilm metabolism on resin composite. Dent Mater 32:1263-9
Zhou, P; Liu, J; Merritt, J et al. (2015) A YadA-like autotransporter, Hag1 in Veillonella atypica is a multivalent hemagglutinin involved in adherence to oral streptococci, Porphyromonas gingivalis, and human oral buccal cells. Mol Oral Microbiol 30:269-79
Chen, Xi; Liu, Nan; Khajotia, Sharukh et al. (2015) RNases J1 and J2 are critical pleiotropic regulators in Streptococcus mutans. Microbiology 161:797-806
Kreth, Jens; Liu, Nan; Chen, Zhiyun et al. (2015) RNA regulators of host immunity and pathogen adaptive responses in the oral cavity. Microbes Infect 17:493-504
Liu, Nan; Niu, Guoqing; Xie, Zhoujie et al. (2015) The Streptococcus mutans irvA gene encodes a trans-acting riboregulatory mRNA. Mol Cell 57:179-90
Merritt, Justin; Chen, Zhiyun; Liu, Nan et al. (2014) Posttranscriptional regulation of oral bacterial adaptive responses. Curr Oral Health Rep 1:50-58
Yoneda, Saori; Loeser, Brandon; Feng, Joseph et al. (2014) Ubiquitous sialometabolism present among oral fusobacteria. PLoS One 9:e99263
Xie, Zhoujie; Qi, Fengxia; Merritt, Justin (2013) Development of a tunable wide-range gene induction system useful for the study of streptococcal toxin-antitoxin systems. Appl Environ Microbiol 79:6375-84

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