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.

Characterization of recombinant wild-type and nontoxigenic protein A from Staphylococcus pseudintermedius

“…Unfortunately, staphylococcal infection does not usually establish protective immunity [24,30–32] and efficacious staphylococcal vaccines have proven difficult to develop. Most vaccine research has focused on S. aureus , which most commonly affects humans and is distinguished from S. pseudintermedius , which is primarily of veterinary concern.…”

Diverted on the way to memory

“…However, it has been shown in a mouse model that protein A contributes significantly to immune evasion 8 and that mono clonal antibodies against protein A neutralize the Fc-binding and Fab-binding activities of protein A 9 . These studies suggest that protein A would be a valuable target for the development of vaccines against S. aureus.…”

Diaryltriazenes as antibacterial agents against methicillin resistant Staphylococcus aureus (MRSA) and Mycobacterium smegmatis

“…Resistant isolates (identified as Isolates R1, R2, and R3) were compared to the parental (control) strain, allowing the genetic polymorphisms differentiating these isolates to be identified ( Figure 3). 27 This molecule consists of a hydrophobic Cterminal, thought to be embedded within the cell membrane, flanked at the N-terminal end by a charged tail. 28,29 The mechanism by which this protein reduces its sensitivity to the diaryltriazene 16a therefore remains unclear; its surface location could however affect the interaction or permeability of the cell to this compound.…”