ROLE OF SAER/S DURING S AUREUS PATHOGENESIS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Staphylococcus aureus (S. aureus) is a leading cause of human infections worldwide and causes a variety of diseases ranging in severity from mild to life-threatening. The ability of S. aureus to cause disease is based in part on its ability to subvert the innate immune system. Recent studies suggest S. aureus evades killing by human polymorphonuclear leukocytes (PMNs or neutrophils). However, relatively little is known about how pathogens detect components of the innate immune system to respond and survive within the host. Therefore, the long term goal of this study is to gain a better understanding of S. aureus pathogenesis. The specific hypothesis is that the S. aureus two  component gene regulatory systems saeR/S facilitates evasion of innate host defenses by S. aureus and is therefore important for pathogenesis. To date Dr. Voyich's lab has generated an isogenic saeR/S deletion mutant in S. aureus strain MW2 (pulse-field type USA400). During PMN interaction the saeR/S mutant was greatly attenuated in its ability to evade killing by human PMNs. Oligonucleotide microarrays indicate saeR/S influences a significant amount of genes of the S. aureus virulon. Deletion of saeR/S significantly attenuated staphylococcal virulence in a mouse model of bacteremia. In contrast, they saw no significant differences in ability between MW2 and the mutant saeR/S strain to cause abscess formation. In summary, saeR/S plays an important role in evasion of killing by PMNs and appears to be a critical factor conferring virulence during S. aureus bacteremia.