Affiliation:
1. Department of Microbiology, University of Chicago, Chicago, Illinois, USA
Abstract
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 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
.
Publisher
American Society for Microbiology
Cited by
199 articles.
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