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. Methicillin-resistant Staphylococcus aureus (MRSA) is problematic both in hospitals and in the community and is now a major cause of human mortality, as an estimated 18, 650 deaths were associated with invasive MRSA infections during 2005 in the United States alone. In recent years, there has been an increase in the incidence of community-associated methicillin-resistant S. aureus (CA-MRSA) infections in healthy individuals. These emerging strains cause skin and soft-tissue infections, but the most prominent strains have also been associated with severe pathology, including sepsis, necrotizing pneumonia, and necrotizing fasciitis. The long-term objective of this proposal is to define the pathogen and host factors contributing to invasive staphylococcal disease. To that end, we have investigated the influence of the SaeR/S two-component gene-regulatory system on invasive staphylococcal disease. We hypothesize that cytolytic factors influenced by the SaeR/S regulatory system of S. aureus promote an inflammatory host response, resulting in the severe pathology seen in invasive staphylococcal infection. This hypothesis is based on preliminary findings demonstrating: 1) significantly attenuated survival of a saeR/S mutant strain (MWdelta saeR/S) after PMN phagocytosis;2) absence of mortality and morbidity in a mouse model of invasive infection in mice infected with MWdelta-saeR/S;and 3) evidence of saeR/S altering gene expression in a wide variety of genes with diverse functions including those involved in evasion of phagocytosis, and virulence. Based on these results, three Specific Aims are designed to provide a comprehensive assessment of the role of saeR/S during invasive staphylococcal disease.