Staphylococcus aureus is a widely disseminated human pathogen whose virulence is associated with a broad range of severe and potentially fatal health complications. It has been shown to produce a series of immunomodulators that promote virulence by affecting both arms of the host immune response. Complement (C’) represents a key innate immune effector that protects against infection, and S. aureus has evolved several strategies to evade C’ neutralization. C’ proteins are essential for the propagation of host inflammatory reactions to bacterial infection and serve as attractive targets for the dampening of this response by pathogens. Indeed, several S. aureus-secreted proteins have been described to have C’ inhibitory activity. To this date, no systematic research effort has been placed on the development of complement-based antimicrobial therapeutics that might exploit immune evasion mechanisms of S. aureus. The current proposal focuses on dissecting critical interactions of S. aureus immune evasion molecules with key components of the innate immune response (complement and cytokine networks) by means of antibody-targeted studies on virulence and inflammation. Our research aims to: 1. Characterize antibodies from S. aureus-exposed individuals that recognize key microbial evasion targets and can attenuate inflammation in a whole blood model of S. aureus-induced bacteremia. Studies will also focus on dissecting the neutralizing capacity of these antibodies on a broad spectrum of inflammatory mediators triggered by bacterial infection. 2. Develop single-chain antibodies against S. aureus proteins identified in Aim 1 as being targets for pathogen neutralization by phage library approaches. The therapeutic efficacy of these library-generated antibodies will be evaluated in in vitro models of inflammation and in vivo mouse models of sepsis. These studies are anticipated to provide a framework for the design of novel antibody-based therapeutics for infectious diseases