Insights into the ArlR/S mediated pathogenesis of Staphylococcus aureus
Meyer, Susan Irene.
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Staphylococcus aureus (S. aureus) is a gram-positive pathogen capable of causing a wide range of disease from relatively simple soft tissue infections to severe life-threatening disease like sepsis and endocarditis. Historically, most S. aureus infections were associated with healthcare settings and a majority of cases were seen in patients with compromised immune systems. In the past decade, however, infections caused by S. aureus have become more common in healthy individuals. These community-associated strains are an even bigger problem because a large percentage are resistant to antibiotics and are have an incredible ability to incur antibiotic resistance. The ability of this bacterium to subsist and thrive in a wide range of environmental conditions is partly due to the pathogen's use of two-component signal transduction gene-regulatory systems that have the ability to sense external conditions and regulate gene transcription appropriately. This study investigates the role of one of these two-component regulatory systems, ArlR/S. An isogenic deletion mutant of the arlR/S operon was created and was tested in several in vitro assays as well as in vivo murine models of infection. Using in murine models of soft tissue infection and invasive infection, it was determined that arlR/S is important to the virulence of S. aureus. A murine model of dissemination showed that S. aureus dissemination is altered with the deletion of the ArlR/S two-component regulatory system. To determine whether the decreased pathogenicity was caused by a change in the interaction between S. aureus and immune cells of the body, in vitro assays with human whole blood and human PMNs were performed with both S. aureus and bacterial supernatants. Interestingly, no differences were seen between the wild type S. aureus and the mutant in these assays. An oligonucleotide microarray was performed and showed strong regulation of ebh (ECM-binding protein homologue), which codes for the giant staphylococcal surface protein (GSSP). Together, this study demonstrates the importance of arlR/S to the regulation of ebh and to the virulence of S. aureus in a PMN-independent manner.