Infection of host tissues by Staphylococcus aureus and S. epidermidis requires an unusual family of staphylococcal adhesive proteins that contain long stretches of serine-aspartate dipeptide-repeats (SDR). The prototype member of this family is clumping factor A (ClfA), a key virulence factor that mediates adhesion to host tissues by binding to extracellular matrix proteins such as fibrinogen. However, the biological siginificance of the SDR-domain and its implication for pathogenesis remain poorly understood. Here, we identified two novel bacterial glycosyltransferases, SdgA and SdgB, which modify all SDR-proteins in these two bacterial species. Genetic and biochemical data demonstrated that these two glycosyltransferases directly bind and covalently link N-acetylglucosamine (GlcNAc) moieties to the SDR-domain in a step-wise manner, with SdgB appending the sugar residues proximal to the target Ser-Asp repeats, followed by additional modification by SdgA. GlcNAc-modification of SDR-proteins by SdgB creates an immunodominant epitope for highly opsonic human antibodies, which represent up to 1% of total human IgG. Deletion of these glycosyltransferases renders SDR-proteins vulnerable to proteolysis by human neutrophil-derived cathepsin G. Thus, SdgA and SdgB glycosylate staphylococcal SDR-proteins, which protects them against host proteolytic activity, and yet generates major eptopes for the human anti-staphylococcal antibody response, which may represent an ongoing competition between host and pathogen.
Staphylococcus aureus and S. epidermidis are major bacterial pathogens that can cause life-threatening human diseases. Following entry into the circulation, S.aureus can infect virtually any organ. However, it must first counter antibacterial mechanisms of the innate immune system, including those involving macrophages and neutrophils. Important for staphylococcal adhesion to and successful colonization of host tissues, is a family of bacterial surface proteins containing multiple repeats of serine-aspartate repeats (SDR) adjacent to an adhesive A-domain. The biological functions of the SDR-domain of these SDR proteins remain elusive. We found that the SDR-domain of all staphylococcal SDR proteins is heavily glycosylated. We identified two novel glycosylases, SdgA and SdgB, which are responsible for glycosylation in two steps, and found that this glycosylation protects the adhesive SDR proteins against proteolytic attack by human neutrophil cathepin G. Since pathogen binding to human tissues, including the extracellular matrix protein fibrinogen, depends on SDR proteins, this glycosylation may be important for successful colonization of the human host. We also show that the SdgB-mediated glycosylation creates an immunodominant epitope for highly opsonic antibodies in humans. These antibodies account for a significant proportion of the total anti-staphylococcal IgG response.