Protein A (SpA) is a conserved surface component of all S. aureus strains, consisting of a N-terminal IgG binding domain, an Xr or short sequence repeat (SSR) region and a C-terminal anchor to the bacterial cell wall. SpA has long been characterized by its anti-phagocytic effect through the interaction with the Fc component of immunoglobulin G. It was later demonstrated that SpA binds to the Fab region of IgM bearing VH3 heavy chains displayed on the surface of B cells acting as a superantigen.
We have recently shown that SpA has a key role in stimulating airway inflammation through its ability to bind and signal through TNF receptor 1 (TNFR1). TNFR1 signalling initiates epithelial production of IL-8 and PMN recruitment to the lungs. Protein A-TNFR1 interaction is essential for the pathogenesis of pneumonia as TNFR1 null mice are not susceptible to S. aureus pneumonia and protein A-defective mutants of S. aureus do not cause infection in wild-type mice.
TNFR1 signalling is regulated through the cleavage of the ectodomain of the receptor by the TNF converting enzyme (TACE). Shedding of TNFR1 from the surface of airway epithelial cells is induced by protein A shortly after the initial pro-inflammatory signalling and the interaction of SpA with the epidermal growth factor receptor (EGFR) and subsequent activation of erk1/2 MAPK is sufficient to induce TACE activity. Thus, staphylococcal recognition of EGFR and activation of TACE serves to counteract the pro-inflammatory consequences of TNFR1 signalling, PMN recruitment and activation.
We determined that the above mentioned biological functions of SpA are all localized to the N-terminal region within the IgG binding domains. Adjacent to these domains of SpA is a well characterized region consisting of 24 bp SSR of varying numbers and sequences which is the basis of the spa typing system. The function of these repeated sequences despite their widespread conservation has been entirely unclear. We demonstrated that the Xr domain potently activates type I interferon signalling in airway epithelial cells. Xr mediates endocytosis of protein A, activation of IFN-β, Jak-STAT signalling and IL-6 production via a TLR4 dependent process. Increased numbers of the 24 bp repeats are associated with a dose-dependent increase in IL-6 and PMN recruitment into the murine lung. The ability of S. aureus to modulate type I interferon and TNF immune responses through the protein A locus is likely to contribute to its success as a pathogen.