MODULATORS OF PNEUMOCOCCAL ADHESION TO CELLULAR TARGETS INVOLVING THE PLATELET ACTIVATING FACTOR RECEPTOR, AND USES THEREOF

摘要

The present invention relates to compositions and methods for preventing pneumococcal infection. In particular, the invention relates to identification of the major reception for Streptococcus pneumoniae on activated human cells, and diagnostic and therapeutic compositions and methods based thereon. In particular, the invention relates to the discovery that platelet activating factor (PAF) receptor is an adhesive ligand for pneumococcal adherence to activated lung epithelial and venous endothelial (i.e., host) cells. Accordingly, the present invention is directed to a method for preventing or treating an infection with Streptococcus pneumoniae by administering an antagonist of platelet activating factor receptor. The invention further relates to recognition that adherence to activated cells also involves a carbohydrate ligand found on such activated cells. Thus, a method for inhibiting pneumococcal adherence may further comprise administering an amount of carbohydrate containing an N-acetyl-D-glucosamine motif. It has been found that resting lung epithelial and venous endothelial cells bear two classes of receptors containing different carbohydrate motifs. Thus, the invention further provides for administering an amount of a second carbohydrate selected from the group consisting of a carbohydrate containing a disaccharide N-acetyl-D-galactosamine beta 1-4Gal motif, a disaccharide N-acetyl-D-galactosamine beta 1-3Gal motif, and a mixture thereof. In addition, the invention provides pharmaceutical compositions comprising such agents that inhibit binding of pneumococci to human cells. In a specific example, platelet activating factor receptor antagonists and disaccharides are shown to inhibit binding of pneumococci to activated lung epithelial cells and venous endothelial cells, as well as cells transfected with the platelet activating factor receptor, in vitro.