(from abstract) Bacterial keratitis caused by Pseudomonas aeruginosa is a severe ocular infection that can progress rapidly, resulting in intense ocular inflammation, irreversible stromal scarring of the cornea, blindness, and the need for corneal transplantation. The objective of this project is to improve our understanding of both the bacterial factors and the host immune and nonimmune factors that contribute to stromal damage, as a basis for the development of a chemotherapeutic regimen that prevents corneal scarring. Although intense antibiotic therapy of Pseudomonas keratitis kills the bacteria and sterilizes the cornea, damage still occurs; scarring results from a sequence of cellular changes mediated by an inflammatory response in the host cornea. Thus, any therapy, to be clinically successful, must inhibit both bacterial and host factors. Therefore, the specific aims are to test hypotheses concerning the nature of and the contributions of host factors and bacterial factors to corneal inflammation and tissue damage, as well as the mechanisms that must be controlled to reduce scarring. Proposed experiments, both in vitro and in vivo, will 1) define the pathogenic role of bacterial exoproteins in the host tissues, especially proteases; 2) assess combination chemotherapy of keratitis using antibiotics to limit production of bacteria and nonsteroidal anti-inflammatory drugs (NSAID) to inhibit inflammation-mediated stromal damage; 3) evaluate protease inhibitors as chemotherapeutic agents to reduce the ability of bacterial and host proteases to mediate tissue damage; and 4) test new chemotherapeutic regimens using antibiotics in various combinations that include NSAIDs, steroids, and protease inhibitors in order to simultaneously inhibit both host and bacterial factors. Methods include the use of wild-type Pseudomonas strains compared to exoprotein-deficient Pseudomonas strains in order to identify the specific proteins that produce corneal damage, and the use of recently identified Pseudomonas proteases in order to identify and test appropriate protease inhibitors.
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