Role of Protein A in the Evasion of Host Adaptive Immune Responses by Staphylococcus Aureus.

ABSTRACTHeritable defects in human B cell/antibody development are not associated with increased susceptibility toStaphylococcus aureusinfection. Protein A (SpA), a surface molecule ofS. aureus, binds the Fcγ domain of immunoglobulin (Ig) and cross-links the Fab domain of VH3-type B cell receptors (IgM). Here we generatedS. aureus spavariants harboring amino acid substitutions at four key residues in each of the five Ig-binding domains of SpA. Wild-typeS. aureusrequired SpA binding to Ig to resist phagocytosis and SpA-mediated B cell receptor cross-linking to block antibody development in mice. ThespaKKAAmutant, which cannot bind Ig or IgM, was phagocytosed and elicited B cell responses to key virulence antigens that protected animals against lethalS. aureuschallenge. The immune evasive attributes ofS. aureusSpA were abolished in µMT mice lacking mature B cells and antibodies. Thus, while wild-typeS. aureusescapes host immune surveillance, thespaKKAAvariant elicits adaptive responses that protect against recurrent infection.IMPORTANCEStaphylococcus aureuscauses recurrent skin and bloodstream infections without eliciting immunity. Heritable defects in neutrophil and T cell function, but not B cell or antibody development, are associated with increased incidence ofS. aureusinfection, and efforts to develop antibody-basedS. aureusvaccines have thus far been unsuccessful. We show here that the Fcγ and VH3-type Fab binding activities of staphylococcal protein A (SpA) are essential forS. aureusescape from host immune surveillance in mice. The virulence attributes of SpA in mice required mature B cells and immunoglobulin. These results suggest that antibodies and B cells play a key role in the pathogenesis of staphylococcal infections and provide insights into the development of a vaccine againstS. aureus.