title: Role of protein A in the evasion of host adaptive immune responses by Staphylococcus aureus.
abstract: Heritable defects in human B cell/antibody development are not associated with increased susceptibility to Staphylococcus aureus infection. Protein A (SpA), a surface molecule of S. aureus, binds the Fcγ domain of immunoglobulin (Ig) and cross-links the Fab domain of VH3-type B cell receptors (IgM). Here we generated S. aureus spa variants harboring amino acid substitutions at four key residues in each of the five Ig-binding domains of SpA. Wild-type S. aureus required SpA binding to Ig to resist phagocytosis and SpA-mediated B cell receptor cross-linking to block antibody development in mice. The spaKKAA mutant, which cannot bind Ig or IgM, was phagocytosed and elicited B cell responses to key virulence antigens that protected animals against lethal S. aureus challenge. The immune evasive attributes of S. aureus SpA were abolished in µMT mice lacking mature B cells and antibodies. Thus, while wild-type S. aureus escapes host immune surveillance, the spaKKAA variant elicits adaptive responses that protect against recurrent infection.
  
  
  OBJECTIVE
  Staphylococcus aureus causes 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 of S. aureus infection, and efforts to develop antibody-based S. aureus vaccines have thus far been unsuccessful. We show here that the Fcγ and VH3-type Fab binding activities of staphylococcal protein A (SpA) are essential for S. aureus escape 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 against S. aureus.
authors: Department of Microbiology, University of Chicago, Chicago, Illinois, USA.
authors: Fabiana
authors: F
authors: Falugi
authors: Hwan Keun
authors: HK
authors: Kim
authors: Dominique M
authors: DM
authors: Missiakas
authors: Olaf
authors: O
authors: Schneewind
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D005260:Female; D006801:Humans; D057131:Immune Evasion; D051379:Mice; D008807:Mice, Inbred BALB C; D013203:Staphylococcal Infections / Q000276:immunology* / Q000382:microbiology; D013205:Staphylococcal Protein A / Q000235:genetics / Q000276:immunology*; D013211:Staphylococcus aureus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D014774:Virulence
chemical_list: D013205:Staphylococcal Protein A
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