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Ivelisse Rodriguez-Pagan, John Chen, Gregory A. Wasserman, Richard P. Novick, Michael Engelbert; agr, A Global Regulator Of Virulence Is A Determinant Of Pathogenesis In Experimental Endophthalmitis Caused Community Acquired Epidemic S. aureus Strain USA300. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2771.
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To determine the contribution of agr to the pathogenesis of the community-associated methicillin-resistant S. aureus (MRSA) strain USA300 in the murine model of endophthalmitis.
The vitreous of C57/Bl6 mice was injected with 2,700 (n=10) and 7,700 cfu (n=10) of a derivative of USA300-LAC with an agrp3-lux reporter (WT) to monitor the activation of agr by bioluminescence assay during the course of infection. Another 10 mice were infected with 5,100 cfu of an isogenic knockout in the agr locus (KO). Electroretinography for retinal function, plate counts of ocular homogenates for bacterial numbers, and histopathology for anatomical outcome at various time points during the infection were used to compare outcome of infection with 2,700 cfu WT and 5,100 cfu KO.
In eyes infected with 7,700 cfu WT, agr activation was first detected at 8 hours. Activation was maintained in many of the eyes infected with 2,200 cfu for the entire 72 hours studied (6 out of 10). Retinal function at 24 hours was significantly higher in eyes infected with 5,100 cfu KO compared to the eyes infected with 2,200 cfu WT (32 ± 16 % and 17 ± 19 % retinal function; p=0.04 Mann Whitney U, respectively). Retinal function was abolished by 48 hours in most of the WT infected eyes (6 out of 10, 17 ± 23 % retinal function). Perforation of the eye was rare, but reproducible in WT infected eyes. In contrast, almost all KO infected eyes retained some retinal function over the entire 72 hours of infection (7 out of 10, 32 ± 19 % retinal function). None of the KO infected eyes perforated and the clinical picture was milder overall than in the WT infected eyes. Interestingly, bacterial numbers at 72 hours were not significantly different in the two groups (WT, 5.2 ± 8.5 x 108 versus KO, 1.1 ± 2 x 106; p=0.28 Mann Whitney U). While WT infected eyes showed complete disorganization of the retina and invasion of S. aureus into various intraocular structures by 72 hours (n=2), the KO infected eyes had relative preservation of retinal architecture except for outer retinal undulation (n=2).
The agr KO compared to WT USA300 had an overall milder clinical picture of infection as measured by external exam, retinal function, and histopathology. agr appears to be an important virulence factor in the epidemic MRSA strain USA300.
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