THE SAER/S SYSTEM OF S AUREUS: SENSING AND RESPONDING TO INNATE IMMUNITY

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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. The highly adaptable pathogen is the causative agent of diverse diseases ranging from superficial skin abscesses to life-threatening diseases. The ability of S. aureus to adapt to varied environments is dependent on complex accessory gene systems, including those involved in virulence/pathogenesis. Expression of these accessory gene systems is tightly controlled by transcriptional regulatory networks, including two-component signal transduction systems. Nevertheless, how the pathogen senses and responds to different environmental cues during invasion of the human host is not well understood. Thus, Dr. Voyich's long-term goal is to gain a better understanding of mechanisms of S. aureus pathogenesis. Dr. Voyich's preliminary studies suggest the ability of S. aureus to cause disease is based in part on its ability to evade our innate immune system. More specifically, S. aureus can avert destruction by one of the most potent effectors of innate immunity, the polymorphonuclear leukocyte (PMN or neutrophil). Based on preliminary findings, Dr. Voyich hypothesizes that the S. aureus two-component regulatory system saeR/S triggers pathogen-protective responses to innate host defense(s). This hypothesis is based on the following key observations: (1) saeR/S was highly up-regulated during PMN phagocytosis (86), (2) deletion of saeR/S in the virulent community-associated strain MW2 (pulse-field type USA 400) significantly attenuated survival during PMN phagocytosis (3) deletion of saeR/S significantly attenuated virulence in a mouse model of sepsis. Collectively, these data suggest that saeR/S is triggered by a PMN component(s) and genes under its influence are necessary for PMN evasion and sepsis.