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S. R. Heimer, A. Yamada, M. S. Gilmore; The Impact of Staphylococcus Aureus Toxins on the Proinflammatory and Stress Responses of Human Corneal Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2008;49(13):499.
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© ARVO (1962-2015); The Authors (2016-present)
Staphylococcus aureus is an opportunistic pathogen capable of producing keratitis in some instances of non-surgical traumas to the eye and contact lens wear. It is speculated that compromises in the epithelial layer of the cornea make it vulnerable to colonization by S. aureus. The ensuing corneal pathology is mediated by the host immune response and lytic bacterial toxins. However, S. aureus toxins at sub-lethal concentrations can also affect the infection outcome by modulating cell behavior i.e. receptor processing and intracellular signaling events. Little is known regarding the effects of toxins on corneal epithelium behavior. The objective of this study is to determine if sub-lethal concentrations of Agr/Sar-regulated toxins derange the response of corneal epithelial cells to the presence of adherent S. aureus.
Confluent monolayers of human corneal epithelial cells (hCE: primary and Araki-Sasaki) were infected for 6hrs with small inoculums of S. aureus strain RN6390 or ALC135, an isogenic, non-toxigenic mutant. Infected cultures were evaluated for changes in transcriptional, translational, and secretion patterns relative to uninfected controls using Affymetrix Gene Chip U133 Plus 2.0, western blots, enzyme-linked immunosorbent assays, and multiplex arrays.
The principle transcriptional response of hCE (Araki-Sasaki) to adherent S. aureus was the induction of genes encoding proinflammatory chemokines and cytokines such as CCL20, IL8, CSF2, GRO1, and IL6. Significant increases in transcription were also observed in genes encoding regulatory components of the MAPK and TGFβ-signaling pathways. Increased secretion of the proinflammatory factors was confirmed in the culture supernatants of infected primary corneal and Araki-Sasaki cell lines. Toxin production affected secretion in a subset of these proinflammatory factors but did not alter the transcript levels. S. aureus toxins were associated with upregulation of several stress-related genes, such as HSPA6, HSPA1.AB, DNAJ.B1, CRYAB, and PHLDA2. Comparable responses were minimal or absence in infections involving the non-toxigenic strain.
In addition to being a protective barrier, the corneal epithelium generates proinflammatory signals during early stages of S. aureus infections. Interestingly, S. aureus toxins can influence the production of some proinflammatory signals in a post-transcriptional manner. Moreover, the toxins induce a response in the transcriptome which is characteristic of endoplasmic reticulum stress.Acknowledgments: NEI #017381-01A1 and Japanese Eye Bank Society
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