Pseudomonas aeruginosa causes a devastating form of keratitis that is typically contact lens associated. Progress in lens development to allow more oxygen penetration, according to new preliminary clinical studies, has not prevented Gram-negative bacterial keratitis. Studies of experimental Pseudomonas keratitis indicate that corneal damage is mediated by the action of bacterial proteins that, once released into the tissue, continue to act free of inhibition by antibiotics or other drugs now in existence. Of the multiple proteins produced by Pseudomonas, the ? one that has been best shown to be the """"""""aggressin"""""""" that mediates corneal damage is protease IV. This protease is only produced by P. aeruginosa and every strain tested to date produces this enzyme. Bacterial genetic experiments have demonstrated that the production of this enzyme provides substantial corneal virulence. ? Given the problem of Pseudomonas keratitis and the proven importance of bacterial proteins in the pathogenesis, a long-term goal is to develop a means to inhibit the aggressin proteins that damage the cornea once they are produced by intra-corneal bacteria. Toward that goal, the following specific aims are proposed: 1) develop an antibody capable of neutralizing protease IV and use this antibody as passive immunization to minimize corneal damage (this approach has been effective for Staphylococcus keratitis); 2) quantify the contribution of other proteases, including two uncharacterized enzymes, to corneal pathology to determine if they too should be targets for protective immunotherapy; 3) determine the host molecules, including host defense molecules, that are destroyed by bacterial proteins during infection; and 4) determine the importance of specific bacterial proteins to the host responses that typify Pseudomonas keratitis. These host responses to be analyzed include activation of matrix metalloproteinases, production of inflammatory cytokines, and increases in comeal calcium concentration. Critical to this research are the recent development of Pseudomonas putida strains that produce individual gene products of P. aeruginosa. These engineered strains can infect and replicate in the rabbit cornea without causing corneal damage unless the cloned genes of P. aeruginosa are produced. ? ? ?
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