Abstract
Staphylococcus aureus causes reiterative and chronic persistent infections. This can be explained by the formidable ability of this pathogen to escape immune surveillance mechanisms. Cells of S. aureus display the abundant staphylococcal protein A (SpA). SpA binds to immunoglobulin (Ig) molecules and coats the bacterial surface to prevent phagocytic uptake. SpA also binds and cross-links variable heavy 3 (VH3) idiotype (IgM) B cell receptors, promoting B cell expansion and the secretion of nonspecific VH3-IgM via a mechanism requiring CD4+ T cell help. SpA binding to antibodies is mediated by the N-terminal Ig-binding domains (IgBDs). The so-called region X, uncharacterized LysM domain, and C-terminal LPXTG sorting signal for peptidoglycan attachment complete the linear structure of the protein. Here, we report that both the LysM domain and the LPXTG motif sorting signal are required for the B cell superantigen activity of SpA in a mouse model of infection. SpA molecules purified from staphylococcal cultures are sufficient to exert B cell superantigen activity and promote immunoglobulin secretion as long as they carry intact LysM and LPXTG motif domains with bound peptidoglycan fragments. The LysM domain binds the glycan chains of peptidoglycan fragments, whereas the LPXTG motif is covalently linked to wall peptides lacking glycan. These findings emphasize the complexity of SpA interactions with B cell receptors.IMPORTANCE The LysM domain is found in all kingdoms of life. While their function in mammals is not known, LysM domains of bacteria and their phage parasites are associated with enzymes that cleave or remodel peptidoglycan. Plants recognize microbe-associated molecular patterns such as chitin via receptors endowed with LysM-containing ectodomains. In plants, such receptors play equally important roles in defense and symbiosis signaling. SpA of S. aureus carries a LysM domain that binds glycan strands of peptidoglycan to influence defined B cell responses that divert pathogen-specific adaptive immune responses.
Highlights
Staphylococcus aureus causes reiterative and chronic persistent infections
Earlier work demonstrated that staphylococcal secretion of staphylococcal protein A (SpA) encompassing four or five Ig-binding domains (IgBDs) is essential for B cell superantigen activity [12]
Full-length SpA and SpADXr and SpALysM, lacking the C-terminal Xr and lysin motif (LysM) domains, respectively, displayed similar fractionation profiles, with most of the proteins found in the cell wall (Fig. 1B)
Summary
Staphylococcus aureus causes reiterative and chronic persistent infections. This can be explained by the formidable ability of this pathogen to escape immune surveillance mechanisms. The LysM domain binds the glycan chains of peptidoglycan fragments, whereas the LPXTG motif is covalently linked to wall peptides lacking glycan These findings emphasize the complexity of SpA interactions with B cell receptors. During infection of mice and humans, B cell superantigen activity leads to the expansion of VH3 idiotype plasmablasts in blood and to the secretion of VH3 idiotype antibodies that lack recognition of staphylococcal antigens [12, 14] In this manner, SpA may contribute to the lifelong association of S. aureus with humans and the bacterium’s ability to cause reiterative infections [15]. Native SpA released from the staphylococcal cell wall, but not recombinant SpA purified from the cytoplasm of Escherichia coli, is sufficient to induce the expansion of VH3 idiotype IgG and IgM in mice [12]
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