Staphylococcus aureus is a leading cause of nosocomial and community acquired infections. The organism owes its ability to cause disease to the production of a repertoire of virulence factors and antibiotic resistance determinants, as well as its adaptability to environmental challenges. Our long- term goal is to define the regulatory mechanisms controlling S. aureus pathogenicity. Classically, S. aureus virulence factor expression has been considered to be regulated at the level of transcript synthesis. The specific hypothesis of this proposal is that S. aureus regulates these factors by modulating their mRNA turnover. This hypothesis is based on the following observations: 1) we have shown that the staphylococcal accessory regulator (sarA) stabilizes virulence factor transcripts in a manner that inversely correlates with protein production, 2) our preliminary data indicates that induction of S. aureus stress responses cause global alterations in mRNA turnover, 3) we have shown that alterations in mRNA decay correlate with changes protein production. 4) Modulation of mRNA turnover is a common mechanism of regulating protein production in other bacterial pathogens.
The specific aims are to: 1. Characterize factors that influence log-phase S. aureus mRNA turnover. We believe that the normal RNA turnover machinery functions can be altered in response to endogenous and exogenous cues. As a prerequisite to determining how these functions are altered, it is crucial to understand the principle components involved in native RNA turnover. 2. Characterize the effects of modulating mRNA stability on protein production. We will assess the functional significance of stress mediated changes in mRNA stability on virulence factor protein production. 3. Identify factors that transiently modulate mRNA turnover. Small non-coding RNA molecules (sRNAs) and RNA binding proteins influence bacterial mRNA turnover and translation. We have determined that S. aureus produces 139 sRNA-like molecules in a growth phase- and/or stress- dependent manner. We will characterize the effects of these molecules on S. aureus mRNA turnover and protein production. Moreover, we will identify additional trans-acting factors that transiently alter S. aureus virulence factor mRNA turnover. Staphylococcus aureus is a leading cause of hospital and community acquired infections. The goal of this proposal is to investigate the mechanism(s) by which the organism, regulates its repertoire of virulence factors and causes disease. Defining these mechanisms is expected to provide novel strategies for therapeutic intervention of S. aureus infections. ? ? ?
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