Immunological studies on staphylococcal superantigen-like proteins
The staphylococcal superantigen-like proteins (SSLs) are a family of polymorphic paralogs encoded within the Staphylococcus aureus genome, whose function remains unknown. The ability of SSL7, and a closely related paralog SSL9, to interact with cells of the immune system was investigated. Within the populations of human white blood cells, both SSLs interact selectively with monocytes, via specific but separate binding sites, leading to rapid uptake of SSLs. In addition, SSLs are rapidly taken up by dendritic cells (DC), but not macrophages, and target the mannose-receptor dependent endosomal antigen processing pathway. The effect of these proteins on the functional capacity of antigen presenting cells to uptake and present antigens to T cells was also determined. Neither SSL was toxic to DCs and the presence of SSL protein did not inhibit the antigen presenting cell activity, in terms of stimulation of either allogeneic or recall T cell responses. The immunological response to the SSL proteins in the normal human population was investigated. More than 30% of healthy normal subjects tested showed T cell responses to both SSL7 and SSL9. Moreover, almost all individuals had specific non- cross reacting antibodies against this family of proteins. In order to identify the SSL receptor(s), affinity chromatography techniques were used to isolate and identify the receptor(s) from selected cell lines. A single specific protein band that may represent the putative SSL receptor was observed, and mass spectrometry identified a candidate binding protein as heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa, GRP78 (BiP)). The presence of eleven members of this protein family within the pathogenicity island SaPIn2 in almost all S. aureus strains tested so far, suggest that these proteins have important non-redundant biological functions as agents of host/pathogen interactions. The data presented in this thesis further suggests that this function may involve targeting the host antigen presenting cell.