Staphylococcus aureus is a leading cause of nosocomial and community associated infections. The organismowes its ability to cause disease to the production of a repertoire of virulence- and antibiotic resistance-determinants, as well as its adaptability to environmental challenges. Our long term goal is to define theregulatory mechanisms that control S. aureus pathogenicity. Classically, S. aureus virulence factor expressionhas been considered to be regulated at the level of transcript synthesis. The specific hypothesis of thisproposal is that S. aureus regulates these factors by modulating their mRNA turnover. This hypothesis isbased on the following observations: 1) we have shown that S. aureus regulates the mRNA turnover of mRNAspecies, including most recognized virulence factors, in response to endogenous and exogenous cues, 2) ourpreliminary data establish that alterations in mRNA decay correlate with changes in protein production, 3) wehave found that the organism produces several molecular components that, by virtue of analogous systems,are likely to transiently affect mRNA turnover, and 4) modulation of mRNA turnover is a common mechanism ofregulating protein production in other bacterial pathogens.
The specific aims of this proposal are:1. Characterize factors that govern log-phase (native) S. aureus mRNA turnover. We believe that the nativeRNA turnover functions can be altered in response to conditions that the organism faces during pathogenesis.As a prerequisite to determining how these functions are altered, it is crucial to understand the principlecomponents of native mRNA turnover; they will be identified.2. Identify factors that transiently modulate mRNA turnover. Small non-coding RNAs (sRNAs), RNA bindingproteins, and RNA degradation machinery auxiliary factors influence mRNA turnover and translation withinother bacterial pathogens. Our preliminary data indicate that several, if not all, of these RNA turnovermodulatory factors exist within S. aureus. We will define the effects of S. aureus sRNA-like molecules onmRNA expression, mRNA turnover and protein production. Moreover, we will identify other trans-acting factorsthat mediate alterations in S. aureus virulence factor mRNA stability.3. Characterize the effects of modulating mRNA stability on virulence factor protein production.

Public Health Relevance

Results of these studies will identify factors that are involved in Staphylococcus aureus disease processes. Inhibiting these factors may yield new therapeutic agents for the treatment of S. aureus infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI073780-05
Application #
8207964
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Huntley, Clayton C
Project Start
2008-09-15
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$378,563
Indirect Cost
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Eidem, Tess M; Lounsbury, Nicole; Emery, John F et al. (2015) Small-molecule inhibitors of Staphylococcus aureus RnpA-mediated RNA turnover and tRNA processing. Antimicrob Agents Chemother 59:2016-28
Price-Whelan, Alexa; Poon, Chun Kit; Benson, Meredith A et al. (2013) Transcriptional profiling of Staphylococcus aureus during growth in 2 M NaCl leads to clarification of physiological roles for Kdp and Ktr K+ uptake systems. MBio 4:
Brinkman, Cassandra L; Bumgarner, Roger; Kittichotirat, Weerayuth et al. (2013) Characterization of the effects of an rpoC mutation that confers resistance to the Fst peptide toxin-antitoxin system toxin. J Bacteriol 195:156-66
Kinkel, Traci L; Roux, Christelle M; Dunman, Paul M et al. (2013) The Staphylococcus aureus SrrAB two-component system promotes resistance to nitrosative stress and hypoxia. MBio 4:e00696-13
Morrison, John M; Miller, Eric W; Benson, Meredith A et al. (2012) Characterization of SSR42, a novel virulence factor regulatory RNA that contributes to the pathogenesis of a Staphylococcus aureus USA300 representative. J Bacteriol 194:2924-38
Eidem, Tess M; Roux, Christelle M; Dunman, Paul M (2012) RNA decay: a novel therapeutic target in bacteria. Wiley Interdiscip Rev RNA 3:443-54
Morrison, John M; Anderson, Kelsi L; Beenken, Karen E et al. (2012) The staphylococcal accessory regulator, SarA, is an RNA-binding protein that modulates the mRNA turnover properties of late-exponential and stationary phase Staphylococcus aureus cells. Front Cell Infect Microbiol 2:26
Roux, Christelle M; DeMuth, Jonathon P; Dunman, Paul M (2011) Characterization of components of the Staphylococcus aureus mRNA degradosome holoenzyme-like complex. J Bacteriol 193:5520-6
Morrison, John M; Dunman, Paul M (2011) The modulation of Staphylococcus aureus mRNA turnover. Future Microbiol 6:1141-50
Truong-Bolduc, Q C; Dunman, P M; Eidem, T et al. (2011) Transcriptional profiling analysis of the global regulator NorG, a GntR-like protein of Staphylococcus aureus. J Bacteriol 193:6207-14

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