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Ama Sadaka, Takashi Suzuki, Kelli Palmer, Michael Gilmore; The role of CodY in S. aureus endophthlamitis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2870.
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© ARVO (1962-2015); The Authors (2016-present)
To define global transcriptional responses of S. aureus and its codY mutant (CodY is a transcription regulator that controls expression of virulence and metabolic genes in response to branched-chain amino acids and GTP) when growing in bovine aqueous (AH) and vitreous humor (VH) in vitro and to interrogate the impact of codY deletion on S. aureus virulence in a novel murine anterior chamber infection model.
For the in vitro model, differential transcriptomic gene expression of S. aureus and its codY mutant grown in chemically defined medium (CDM), AH and VH was analyzed. Furthermore, the strains were inoculated into the anterior chamber of mice. Changes in bacterial growth, electroretinography and slit lamp examination scores were comparatively monitored.
Bovine AH and VH provide sufficient nutrition for growth of S. aureus in vitro. Transcriptome analysis showed 72 unique open reading frames regulated differentially at least 10-fold between CDM, AH, and VH. Among those, genes involved in pseudouridine transport and catabolism, sialic acid catabolism and ascorbate uptake were highly upregulated in AH. Several virulence factors also showed differential regulation. The codY regulon identified during growth in AH and VH overlapped that in CDM, which could be explained by several differences between growth in vitro and in vivo. As for the role of codY in the anterior chamber infection model, we found that comparable growth of the codY mutant and wild type occurred in vivo. Average inflammation scores were significantly worse for codY mutant infected eyes at 24 h. Average retinal responsiveness also was lower for eyes infected with the codY mutant. Complementation of S. aureus codY mutant with the codY gene, showed increased retinal responsiveness and
Our in vitro bovine AH and VH models identified some of the nutrients that S. aureus specifically detects and responds to in the ocular milieu, in particular, sialic acid, ascorbate, and pseudouridine. Whether deletion of genes involved in transport and catabolism of these substrates directly impacts S. aureus growth in vivo and pathogenesis remains to be determined. The in vivo model, suggests that control of nutrition, such as abundance of branched chain amino acids, has the potential to be used therapeutically to limit S. aureus endophthalmitis severity.
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