The Rockefeller University

The Beth Israel Hospital Association

Philadelphia University

Diana R Cundell

Elaine I Tuomanen

Norma P Gerard

Ekaterina Shumilova

Bhalchandra Dhamankar

Alexander A Messinger

Brian R George

The present invention relates to compositions and methods for preventing pneumococcal infection. In particular, this invention relates to the identification of the minimum receptor targets of pneumococcal adherence to pulmonary and vascular endothelium, and to compositions and methods for preventing such adherence. In particular, the invention relates to the ability of one or more carbohydrate entities having the following motif or motifs: a disaccharide N-acetyl-D-galactosamine .beta.1-3Gal motif, a disaccharide N-acetyl-D-galactosamine .beta.1-4Gal motif, and an N-acetyl-D-glucosamine motif, effective to induce elution of adherent S. pneumoniae from host cells. In particular, a composition containing all three motifs can elute about 100% of pneumococcal bacteria from lung epithelial cells, and from venous endothelial cells. In a particular embodiment, a pharmaceutical composition of the invention can be used to treat pneumococcal infections in which the host cells are lung epithelial cells. For use in blocking adherence to, or eluting adherent bacteria from, lung epithelial cells, the pharmaceutical composition is an aerosol formulation. The invention further provides formulations for parenteral administration for treating systemic blood-borne infections by preventing or reversing binding to venous endothelial cells. The invention further relates to methods and kits for determining the presence of pneumococci in a biological sample from a subject.

Modulators of pneumococcal adherence to pulmonary and vascular cells and

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.

Modulators of pneumococcal adhesion to cellular targets involving the

Growing community of inventors

New York, NY, United States of America

Diana R Cundell