ABSTRACT Staphylococcus aureus is a human-adapted pathogen that replicates by asymptomatically colonizing its host. Nasal colonization is observed in the first weeks of life and persists despite the development of serum IgG against staphylococcal antigens. S. aureus is also an invasive pathogen, causing soft tissue, wound, lung, skeletal and bloodstream infections in community- and hospital-settings. Infection with antibiotic-resistant strains, designated methicillin-resistant S. aureus (MRSA), is associated with treatment failure and poor disease outcomes. MRSA and methicillin-sensitive (MSSA) strains are frequent causes of infectious disease morbidity and mortality in the United States. It is not always clear why colonization progresses to infection but such transition indicates that antibody responses elicited upon colonization are not protective. The surface of S. aureus is coated with over 10,000 molecules of Staphylococcal protein A (SpA) linked to peptidoglycan by the Sortase A enzyme. Using genetic and biochemical schemes, we found that peptidoglycan-modified SpA diverts antibodies away from their intended targets by interacting with the Fcg domain of IgG and by blocking complement activation. Thus, surface exposed SpA neutralizes the effector functions of pathogen-specific antibodies, including antibodies elicited by candidate vaccines. SpA is also released from the bacterial envelope and binds the variant heavy chains of VH3-IgM that serves as the B cell receptor (BCR) in approximately half of human B cells. SpA-BCR interactions prevent the development of neutralizing anti-SpA antibodies and instead trigger B cell proliferation and the secretion of VH3-rearranged antibodies with no specificity toward S. aureus. Carefully applied molecular engineering yielded the non-toxigenic SpA* vaccine that elicits SpA-neutralizing antibodies. When tested in our mouse model of colonization that takes advantage of the mouse-adapted strain WU1, we found that SpA* immunization leads to broad spectrum anti-S. aureus immune responses. We presume that some of these antibodies target the colonization factors of S. aureus that we seek to identify in this proposal. We also presume that during colonization SpA diffuses into nasal- associated lymphoid tissues to reprogram their B cell repertoire. Lastly, we will evaluate mechanisms of protection against colonization by examining the contribution of serum opsonophagocytic antibodies and luminal IgA for the nasopharyngeal clearance of S. aureus.