The proposed research continues an interdisciplinary effort to assess the role of bacterial toxins and the host response in determining the course and severity of endophthalmitis. Based on these determinations and characterization of the molecular properties of the toxins involved, novel therapeutic strategies specifically targeting these toxins have been and will be derived and tested. During the initial period of support, a plasmid encoded cytolysin elaborated by many clinical isolates of Enterococcus faecalis was observed to influence significantly the severity of endophthalmitis. Based on a molecular understanding of the structure, activity and activation mechanism of this toxin, two experimental therapies involving the use of specifically inhibitory peptides have been designed for proposed analysis. One of these therapies targets the activation step required for the cytolysin to be converted from a biologically inactive precursor to the active cytolytic species. The second peptide based strategy involves the use of""""""""RGD"""""""" based peptides to block bacterial attachment to sensitive tissues of the retina, a phenomenon believed to result in concentration of the active lysin in proximity to the retina. Because of the emerging importance of """"""""RGD"""""""" domain/integrin interactions in a broad variety of intercellular processes, observations made during this aspect of the study will be of wide ranging interest for a variety of intraocular therapies. Additionally, a novel application of submicroscopic, optically transparent liposomes will be tested for the ability to redirect membrane active toxins away from sensitive ocular structures during endophthalmitis. These experimental therapies are possible because of the application of state- of-the-art molecular biology techniques to characterize the respective toxin and its activities. Molecular characterization of the toxins elaborated by the highly virulent eye pathogen, Bacillus cereus, will be initiated during this research to determine which among a constellation of toxins contribute measurably to endophthalmitis caused by this organism. Based upon comparative studies of the molecular pathogenicity of B. cereus and E. faecalis for the eye, new general principles on the host/parasite interaction in intraocular infection will emerge forming the basis for the design and testing of additional experimental therapies for salvaging vision in these sight threatening infections.
| Sadaka, Ama; Palmer, Kelli; Suzuki, Takashi et al. (2014) In vitro and in vivo models of Staphylococcus aureus endophthalmitis implicate specific nutrients in ocular infection. PLoS One 9:e110872 |
| Van Tyne, Daria; Martin, Melissa J; Gilmore, Michael S (2013) Structure, function, and biology of the Enterococcus faecalis cytolysin. Toxins (Basel) 5:895-911 |
| Suzuki, Takashi; Campbell, Jennifer; Kim, Younghoon et al. (2012) Wall teichoic acid protects Staphylococcus aureus from inhibition by Congo red and other dyes. J Antimicrob Chemother 67:2143-51 |
| Sadaka, Ama; Durand, Marlene L; Gilmore, Michael S (2012) Bacterial endophthalmitis in the age of outpatient intravitreal therapies and cataract surgeries: host-microbe interactions in intraocular infection. Prog Retin Eye Res 31:316-31 |
| Suzuki, Takashi; Swoboda, Jonathan G; Campbell, Jennifer et al. (2011) In vitro antimicrobial activity of wall teichoic acid biosynthesis inhibitors against Staphylococcus aureus isolates. Antimicrob Agents Chemother 55:767-74 |
| Klocke, Julia; Barcia, Rita N; Heimer, Susan et al. (2011) Spontaneous bacterial keratitis in CD36 knockout mice. Invest Ophthalmol Vis Sci 52:256-63 |
| Suzuki, Takashi; Campbell, Jennifer; Swoboda, Jonathan G et al. (2011) Role of wall teichoic acids in Staphylococcus aureus endophthalmitis. Invest Ophthalmol Vis Sci 52:3187-92 |
| Swoboda, Jonathan G; Meredith, Timothy C; Campbell, Jennifer et al. (2009) Discovery of a small molecule that blocks wall teichoic acid biosynthesis in Staphylococcus aureus. ACS Chem Biol 4:875-83 |
| Roux, Agnès; Payne, Shelley M; Gilmore, Michael S (2009) Microbial telesensing: probing the environment for friends, foes, and food. Cell Host Microbe 6:115-24 |
| Whiston, Emily A; Sugi, Norito; Kamradt, Merideth C et al. (2008) alphaB-crystallin protects retinal tissue during Staphylococcus aureus-induced endophthalmitis. Infect Immun 76:1781-90 |
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