Staphylococcus aureus is a leading cause of bacterial keratitis in the United States. Despite prompt and effective antibiotic therapy, this infection can cause corneal scarring that results in blindness or significant loss in visual acuity. No known drug or immune augmentation can prevent these harmful reactions. The long-term goal of this research is to develop therapies to arrest corneal damage and rapidly kill infecting bacteria. Important to contemporary ocular research on Staphylococcus keratitis are findings on the host defense against infection and toxins responsible for tissue damage. The prime host defense in the tear film that protects against corneal infection by Staphylococcus has been identified as phospholipase A2 (PLA2) and inhibition of this bactericidal enzyme has allowed topical infection of the rabbit cornea. Because PLA2 provides a potent innate resistance to infection, lapses in its activity could permit the initiation of infection. Changes in PLA2 activity in response to normal physiologic conditions or to infection, as well as the ability of bacteria to become resistant to this host defense, are important issues in understanding bacterial keratitis that are addressed in Aim 1 of this proposal. The new information on corneal toxins reveals a role for gamma-toxin in corneal damage, a possible synergy between alpha- and gamma-toxins and the activity of an uncharacterized toxin.
Aim 2 focuses on the characterization of gamma-toxin, the possible synergy between gamma- and alpha-toxins, and the protectiveness of the immune response to gamma-toxin. Mediating corneal virulence also is a third toxin, one that has yet to be characterized.
Aim 3 describes plans to characterize this newly recognized toxin with a focus on its role in virulence, the sequence of the gene for the toxin, and the protectiveness of the immune response to this toxin. The goal of Aim 4 is to clone these toxin genes, in either an active or mutated toxoid form, into a non-pathogenic Staphylococcus species. Such bacteria will be used in the cornea to express the single cloned S. aureus product, thus revealing either its specific toxicity or the immune response to its production in the cornea. These experiments are designed to provide both new knowledge and reagents to help arrest the pathology of S. aureus keratitis.
|Arana, Angela M; Bierdeman, Michael A; Balzli, Charles L et al. (2015) Staphylococcus Alpha-Toxin Action on the Rabbit Iris: Toxic Effects and Their Inhibition. Curr Eye Res 40:830-8|
|Weeks, Anastasia C; Balzli, Charles L; Caballero, Armando et al. (2012) Identification and potency of cyclodextrin-lipid inhibitors of Staphylococcus aureus ?-toxin. Curr Eye Res 37:87-93|
|McCormick, Clare C; Caballero, Armando R; Balzli, Charles L et al. (2009) Chemical inhibition of alpha-toxin, a key corneal virulence factor of Staphylococcus aureus. Invest Ophthalmol Vis Sci 50:2848-54|
|O'Callaghan, Richard J; McCormick, Clare C; Caballero, Armando R et al. (2007) Age-related differences in rabbits during experimental Staphylococcus aureus keratitis. Invest Ophthalmol Vis Sci 48:5125-31|
|Girgis, Dalia O; Reed, Julian M; Monds, Kathryn S et al. (2005) Pathogenesis of Staphylococcus in the rabbit anterior chamber. Invest Ophthalmol Vis Sci 46:1371-8|
|Girgis, Dalia O; Sloop, Gregory D; Reed, Julian M et al. (2005) Effects of toxin production in a murine model of Staphylococcus aureus keratitis. Invest Ophthalmol Vis Sci 46:2064-70|
|Dajcs, Joseph J; Thibodeaux, Brett A; Marquart, Mary E et al. (2004) Effectiveness of ciprofloxacin, levofloxacin, or moxifloxacin for treatment of experimental Staphylococcus aureus keratitis. Antimicrob Agents Chemother 48:1948-52|
|Girgis, Dalia O; Sloop, Gregory D; Reed, Julian M et al. (2004) Susceptibility of aged mice to Staphylococcus aureus keratitis. Curr Eye Res 29:269-75|
|Girgis, Dalia O; Sloop, Gregory D; Reed, Julian M et al. (2003) A new topical model of Staphylococcus corneal infection in the mouse. Invest Ophthalmol Vis Sci 44:1591-7|
|Girgis, Dalia O; Dajcs, Joseph J; O'Callaghan, Richard J (2003) Phospholipase A2 activity in normal and Staphylococcus aureus-infected rabbit eyes. Invest Ophthalmol Vis Sci 44:197-202|
Showing the most recent 10 out of 35 publications