Bacillus cereus causes the most explosive and devastating form of post-traumatic or endogenous endophthalmitis that, despite aggressive antibiotic and surgical intervention, almost always results in blindness. The regularity of treatment failures despite aggressive treatment necessitates the identification of the specific virulence factors associated with disease and characterization of the underlying pathogenic mechanisms involved. Preliminary studies employed a highly reproducible and sensitive rabbit model of experimental B. cereus endophthalmitis to analyze pathological events occurring during infection. The model was used in a comparative study of gram-positive endophthalmitis to identify the basis for strain-specific differences in virulence. Retinal damage and inflammation occurred in a pathogen-specific manner, with B. cereus endophthalmitis resulting in migration of organisms throughout the eye, significant retinal destruction, and explosive intraocular inflammation within 18 hours. Intravitreal injection of B. cereus cell walls did not affect retinal responsiveness, but induced significant intraocular inflammation. One cytolytic toxin, hemolysin BL, was found not to contribute to endophthalmitis pathogenesis. However, other as yet unidentified proteins secreted by B. cereus caused significant retinal toxicity and intraocular inflammation, paralleling that observed during a natural infection. Among bacterial causes of ocular infectious disease, B. cereus ranks at the top as one of the most virulent ocular pathogens, but ranks near the bottom in terms of understanding the host/pathogen relationship during infection. To fill this existing information gap, we propose to identify the principle factors responsible for B. cereus intraocular virulence by 1) assessing the retinal toxicity and intraocular inflammogenicity of individual B. cereus secreted products and cell wall constituents, 2) analyzing the intraocular virulence of isogenic mutants deficient in specific B. cereus toxins, and 3) examining the contribution of bacterial intraocular migration to virulence. The experiments outlined in this proposal are designed to identify primary B. cereus virulence determinants and characterize their contribution to the course and severity of disease. Identification and characterization of important virulence factors will provide the basis on which information-based therapeutic agents are developed in order to prevent vision loss during B. cereus endophthalmitis.
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