Journal Article

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

Missiakas, Dominique M., Schneewind, Olaf, Falugi, Fabiana, Kim, Hwan Keun

2013

Overview

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 V H 3-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 spa KKAA 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 spa KKAA variant elicits adaptive responses that protect against recurrent infection. IMPORTANCE 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 V H 3-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 . 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 V H 3-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 .

• Publisher: American Society for Microbiology,American Society of Microbiology
• Subject: Abscesses / Adaptive Immunity / amino acid substitution / Amino acids / Animals / Antibiotics / Antibodies / Antigens / B-Lymphocytes - immunology / blood flow / crosslinking / Fab / Female / Flow cytometry / Humans / Immune Evasion / Immune response / Immune system / Immunoglobulin M / Immunoglobulins / Immunosurveillance / Leukocytes (neutrophilic) / Lymphocytes B / Lymphocytes T / Mice / Mice, Inbred BALB C / monitoring / mutants / Mutation / neutrophils / Nosocomial infections / pathogenesis / Phagocytosis / Protein A / Proteins / receptors / Recurrent infection / Staphylococcal Infections - immunology / Staphylococcal Infections - microbiology / Staphylococcal Protein A - genetics / Staphylococcal Protein A - immunology / Staphylococcus aureus / Staphylococcus aureus - genetics / Staphylococcus aureus - immunology / Staphylococcus aureus - pathogenicity / Staphylococcus infections / T-lymphocytes / vaccine development / Vaccines / Virulence