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Transcription Factor EepR Is Required for Serratia marcescens Host Proinflammatory Response by Corneal Epithelial Cells.

ABSTRACT: Relatively little is known about how the corneal epithelium responds to vision-threatening bacteria from the Enterobacterales order. This study investigates the impact of Serratia marcescens on corneal epithelial cell host responses. We also investigate the role of a bacterial transcription factor EepR, which is a positive regulator of S. marcescens secretion of cytotoxic proteases and a hemolytic surfactant. We treated transcriptomic and metabolomic analysis of human corneal limbal epithelial cells with wild-type bacterial secretomes. Our results show increased expression of proinflammatory and lipid signaling molecules, while this is greatly altered in eepR mutant-treated corneal cells. Together, these data support the model that the S. marcescens transcription factor EepR is a key regulator of host-pathogen interactions, and is necessary to induce proinflammatory chemokines, cytokines, and lipids.

SUBMITTER: Brothers KM

PROVIDER: S-EPMC8300729 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Response of human corneal epithelial cells to the secretomes of wild-type Serratia marcescens and an eepR mutant strain

Project description:The bacterium Serratia marcescens is a common contaminant of contact lens cases and lenses. Serratamolide is one of the secreted hemolytic/cytotoxic factors which contribute to the virulence of this opportunistic pathogen (PMID 22615766). A newly identified transcription factor (eepR) is essential for serratamolide production (PMID 25897029). In the present study, we used immortalized human corneal-limbal epithelial (HCLE) cells (PMID 12766048) as targets for the secreted products of either wild-type (WT) S. marcescens or an isogenic eepR mutant. Microarray data showed that at sub - cytotoxic levels, the secretome of WT bacteria stimulated a > 2-fold response in 712 unique characterized genes. Analysis showed that immune/inflammatory response pathways are significantly enriched in these genes. The scaled response of eepR, ((eepR - control)/(WT â?? control)), was < 0.5 for 418 of these 712 genes (59%). Pathway analysis of these 2-fold attenuated genes confirmed that they too represented immune/inflammatory responses. These data demonstrate that the serratamolide-deficient eepR mutant evokes a much weaker immune/inflammatory response from a clinically relevant cellular target than does the wild-type bacterium. A common batch of HCLE cells was used. Independent preparations of Serratia marcescens secretomes were made for each experiment.

2015-12-31 | E-GEOD-71320 | biostudies-arrayexpress

Innate immune regulation of Serratia marcescens-induced corneal inflammation and infection.

Project description:PurposeSerratia marcescens is frequently isolated from lenses of patients with contact lens-associated corneal infiltrates. In the current study, we examined the role of toll-like receptors (TLRs) and interleukin-1 receptor type 1 (IL-1R1) in S. marcescens-induced corneal inflammation and infection.MethodsThe central corneal epithelium of C57BL/6 and gene knockout mice was abraded, and 1 × 10(7) S. marcescens were added in the presence of a silicone hydrogel contact lens, and we examined corneal inflammation by confocal microscopy and neutrophil enumeration. Viable bacteria were quantified by colony-forming units (CFU).ResultsS. marcescens induced neutrophil recruitment to the corneal stroma, and increased corneal thickness and haze in C57BL/6 mice. Conversely, CFU was significantly lower by 48 hours post infection. In contrast, MyD88(-/-), IL-1R(-/-), TLR4(-/-), and TLR4/5(-/-) corneas infected with S. marcescens had significantly increased CFU, indicating impaired clearance. However, there was no significant difference in CFU among C57BL/6, TIRAP(-/-), and TRIF(-/-) mice. Tobramycin-killed S. marcescens induced corneal inflammation in C57BL/6 mice, which was impaired significantly in MD-2(-/-) mice and in C57BL/6 mice pretreated topically with the MD-2 antagonist eritoran tetrasodium.ConclusionsS. marcescens induces corneal inflammation by activation of TLR4/MD-2/MyD88 and the IL-1R1/MyD88 pathways, which are potential therapeutic targets for inhibition of S. marcescens-induced corneal inflammation.

| S-EPMC3481604 | biostudies-literature

Response of human corneal epithelial cells to the secretomes of wild-type Serratia marcescens and an eepR mutant strain

Project description:The bacterium Serratia marcescens is a common contaminant of contact lens cases and lenses. Serratamolide is one of the secreted hemolytic/cytotoxic factors which contribute to the virulence of this opportunistic pathogen (PMID 22615766). A newly identified transcription factor (eepR) is essential for serratamolide production (PMID 25897029). In the present study, we used immortalized human corneal-limbal epithelial (HCLE) cells (PMID 12766048) as targets for the secreted products of either wild-type (WT) S. marcescens or an isogenic eepR mutant. Microarray data showed that at sub - cytotoxic levels, the secretome of WT bacteria stimulated a > 2-fold response in 712 unique characterized genes. Analysis showed that immune/inflammatory response pathways are significantly enriched in these genes. The scaled response of eepR, ((eepR - control)/(WT – control)), was < 0.5 for 418 of these 712 genes (59%). Pathway analysis of these 2-fold attenuated genes confirmed that they too represented immune/inflammatory responses. These data demonstrate that the serratamolide-deficient eepR mutant evokes a much weaker immune/inflammatory response from a clinically relevant cellular target than does the wild-type bacterium.

2015-12-31 | GSE71320 | GEO

Serratamolide is a hemolytic factor produced by Serratia marcescens.

Project description:Serratia marcescens is a common contaminant of contact lens cases and lenses. Hemolytic factors of S. marcescens contribute to the virulence of this opportunistic bacterial pathogen. We took advantage of an observed hyper-hemolytic phenotype of crp mutants to investigate mechanisms of hemolysis. A genetic screen revealed that swrW is necessary for the hyper-hemolysis phenotype of crp mutants. The swrW gene is required for biosynthesis of the biosurfactant serratamolide, previously shown to be a broad-spectrum antibiotic and to contribute to swarming motility. Multicopy expression of swrW or mutation of the hexS transcription factor gene, a known inhibitor of swrW expression, led to an increase in hemolysis. Surfactant zones and expression from an swrW-transcriptional reporter were elevated in a crp mutant compared to the wild type. Purified serratamolide was hemolytic to sheep and murine red blood cells and cytotoxic to human airway and corneal limbal epithelial cells in vitro. The swrW gene was found in the majority of contact lens isolates tested. Genetic and biochemical analysis implicate the biosurfactant serratamolide as a hemolysin. This novel hemolysin may contribute to irritation and infections associated with contact lens use.

| S-EPMC3353980 | biostudies-literature

Disulfide bonds are required for Serratia marcescens nuclease activity.

Project description:The role of the two disulfide bonds found in the Serratia marcescens nuclease were tested by site directed mutagenesis and were found essential for nuclease activity, although slight residual activity remained. The requirement for disulfide bond formation may play a role in preventing the lethal action of nuclease while in the bacterial cytoplasm.

| S-EPMC334271 | biostudies-other

Genetic dissection of Anopheles gambiae gut epithelial responses to Serratia marcescens.

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| S-EPMC8617612 | biostudies-literature

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2018-05-30 | PXD005225 | Pride

Virulence factor expression by Serratia marcescens during microbial keratitis is regulated by stress response protein GumB

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