Staphylococcus aureus can cause superficial skin infections and, systemic infections that entail spread through the blood stream. The organism expresses several factors that compromise the effectiveness of neutrophils and macrophages, the first line of defence against infection, as well as the subsequent adaptive response mediated by T-cells. S. aureus secretes proteins that inhibit complement activation and neutrophil and T-cell chemotaxis. Furthermore, S. aureus expresses several types of superantigen that corrupt the normal humoral immune response, resulting in anergy and immunosuppression.1) The interaction between S. aureus and host cells or the extracellular matrix is mediated by numerous cell-wall bound adhesins and / or by secreted proteins. The extracellular adherence protein (Eap) is such a secreted protein with a very broad binding repertoire for the extracellular matrix. Recently, we demonstrated a mechanism used by S. aureus to escape the host immune system that was attributed to the very potent anti-inflammatory function of Eap. In particular, we found Eap to undergo a direct interaction with ICAM-1 that resulted in the disruption of integrin LFA-1-dependent neutrophil-endothelial interactions and thereby inflammatory cell recruitment in vitro and in vivo (Nat Med, 2002, 8:687-693). A common clinical feature of S. aureus infected wounds is impaired healing. By using purified Eap as well as an Eap-positive and an Eap-deficient strain we found that Eap may account, at least in parts, for the delayed healing of S. aureus infected wounds. Besides its anti-inflammatory actions, the presence of Eap in wounds also inhibited neovascularization. 2)As the LFA-1/ICAM-1 interaction is also important for the transendothelial migration of T cells, we were prompted to investigate whether Eap could be feasible to interfere with T-cell adhesive mechanisms in autoimmune disease, and in particular, in experimental autoimmune encephalomyelitis (EAE). In vitro, Eap reduced adhesion of peripheral blood T cells to immobilized ICAM-1 as well as their transmigration of TNF-alpha activated human endothelium under static and shear flow conditions. These inhibitory effects were corroborated in two murine models of inflammation. In a delayed-type hypersensitivity model (DTH), both T-cell infiltration and the corresponding tissue edema were significantly reduced by Eap. In addition, administration of either purified or recombinant Eap prevented the development of EAE and markedly decreased infiltration of inflammatory cells into the CNS. Strikingly, intervention with Eap after the onset of EAE suppressed the disease. Thus, our findings indicate that Eap could represent an attractive treatment for autoimmune neuro-inflammatory disorders, such as multiple sclerosis. This hypothesis is worth evaluating in further preclinical and clinical studies. 3) The resemblance of Eap with the C-terminus of a staphylococcal superantigen (the part of superantigens that binds to the TCR) will be further investigated as a potential mechanism for the immunosuppressive role of Eap.4) Eap binds to osteopontin and can tehreby interfere with the interaction of osteopontin with alphavbeta3 integrin. As the latter interaction is crucial for bone metastasis of breast cancer cells, the potential of Eap to block breast cancer metastasis will be evaluated.
