Date of Award

Fall 12-2007

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Sciences

Committee Chair

Dr. Mohammed Elasri

Committee Chair Department

Biological Sciences

Committee Member 2

Dr. Bobby Middlebrooks

Committee Member 2 Department

Biological Sciences

Committee Member 3

Dr. Yan Lin Guo

Committee Member 3 Department

Biological Sciences

Committee Member 4

Dr. Shaio Wang

Committee Member 4 Department

Biological Sciences

Abstract

Staphylococcus aureus is an extraordinarily versatile pathogen causing a plethora of infections ranging from superficial infections to toxemic syndromes to life-threatening conditions. S. aureus has developed resistance to an array of antibiotics like methicillin and vancomycin, forcing the need for development of new drugs to combat staphylococcal infections. S. aureus expresses a wide variety of virulence factors. The virulence factors are either cell-bound proteins (e.g., adhesins) or exoproteins (toxins). The cell-bound proteins are expressed early to establish infection and repressed soon after colonization whereas the exoproteins are repressed early and expressed late during the infection. The coordination of the expression of virulence factors is under the control of several global regulatory systems, of which the two most important regulators are the accessory gene regulator (agr) and the staphylococcal accessory regulator (sarA). The agr system is a quorum sensing system in which the S. aureus cells communicate with each other to coordinate expression of virulence factors. sarA regulates the virulence factors via two pathways, an agr-dependent pathway in which sarA activates agr at the transition between the exponential and post-exponential growth phase and an agr-independent pathway in which sarA regulates virulence factors directly. There are evidence for the existence of important upstream and downstream factors that modulate sarA function. In this study, we identified and characterized a novel regulator msa (modulator of sarA), that regulated the expression of global regulators sarA, agr and several important virulence factors. Since, S. aureus has the ability to attach to native tissue and indwelling medical devices leading to the formation of biofilms, we characterized the role of msa in biofilm formation. Mutation of msa results in delayed biofilm formation. Expression analysis showed that the msa mutant had altered the expression of several genes known to be involved in biofilms. The msa mutant showed an increase in expression of alsS and fnbA and decreased the expression of clfA, at! and icaA. Overall, our results indicate that msa does play a critical role in biofilms. Identification of such novel factors represents potential therapeutic candidate for the prevention and treatment of Staphylococcal infections.

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