Dual Gene Expression Analysis Identifies Factors Associated with Staphylococcus aureus Virulence in Diabetic Mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1015148 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26015870.fastq.gz | Fastqsanger.gz | |||
| SRR26015871.fastq.gz | Fastqsanger.gz | |||
| SRR26015872.fastq.gz | Fastqsanger.gz | |||
| SRR26015873.fastq.gz | Fastqsanger.gz | |||
| SRR26015874.fastq.gz | Fastqsanger.gz |
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Project description:Staphylococcus aureus is a major human pathogen of the skin. The global burden of diabetes is high, with S. aureus being a major complication of diabetic wound infections. We investigated how the diabetic environment influences S. aureus skin infection and observed an increased susceptibility to infection in mouse models of both type I and type II diabetes. A dual gene expression approach was taken to investigate transcriptional alterations in both the host and bacterium after infection. While analysis of the host response revealed only minor changes between infected control and diabetic mice, we observed that S. aureus isolated from diabetic mice had significant increases in the levels of genes associated with translation and posttranslational modification and chaperones and reductions in the levels of genes associated with amino acid transport and metabolism. One family of genes upregulated in S. aureus isolated from diabetic lesions encoded the Clp proteases, associated with the misfolded protein response. The Clp proteases were found to be partially glucose regulated as well as influencing the hemolytic activity of S. aureus Strains lacking the Clp proteases ClpX, ClpC, and ClpP were significantly attenuated in our animal model of skin infection, with significant reductions observed in dermonecrosis and bacterial burden. In particular, mutations in clpP and clpX were significantly attenuated and remained attenuated in both normal and diabetic mice. Our data suggest that the diabetic environment also causes changes to occur in invading pathogens, and one of these virulence determinants is the Clp protease system.
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Project description:Staphylococcus aureus is a major human pathogen of the skin. The global burden of diabetes is high, with S. aureus being a major complication of diabetic wound infections. We investigated how the diabetic environment influences S. aureus skin infection and observed an increased susceptibility to infection in mouse models of both type I and type II diabetes. A dual gene expression approach was taken to investigate transcriptional alterations in both the host and bacterium after infection. While analysis of the host response revealed only minor changes between infected control and diabetic mice, we observed that S. aureus isolated from diabetic mice had significant increases in the levels of genes associated with translation and posttranslational modification and chaperones and reductions in the levels of genes associated with amino acid transport and metabolism. One family of genes upregulated in S. aureus isolated from diabetic lesions encoded the Clp proteases, associated with the misfolded protein response. The Clp proteases were found to be partially glucose regulated as well as influencing the hemolytic activity of S. aureus Strains lacking the Clp proteases ClpX, ClpC, and ClpP were significantly attenuated in our animal model of skin infection, with significant reductions observed in dermonecrosis and bacterial burden. In particular, mutations in clpP and clpX were significantly attenuated and remained attenuated in both normal and diabetic mice. Our data suggest that the diabetic environment also causes changes to occur in invading pathogens, and one of these virulence determinants is the Clp protease system.
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Project description:Diabetic wound infections have poor healing outcomes due to the presence of numerous pathogens in addition to an impaired immune response. Group B Streptococcus (GBS) is one of the most commonly isolated bacteria from diabetic wound infections, but virulence mechanisms GBS uses during these infections have not been investigated. Here, we developed a new murine model of GBS diabetic wound infection to determine how GBS establishes infection and persists in the wound environment. Using dual RNA sequencing, we demonstrate that GBS infection of diabetic wounds triggers an inflammatory response, leading to increased transcript levels of inflammatory cytokines and chemokines as well as markers of neutrophil degranulation such as myeloperoxidase, calprotectin, and elastase. We then confirm that diabetic wounds infected with GBS have significantly higher abundance of Il-1b, KC (CXCL1), myeloperoxidase, calprotectin and elastase in wound tissues than uninfected controls . When examining how GBS adapts to this hyper-inflammatory environment we find that GBS upregulates numerous virulence factors including the surface plasminogen-binding protein pbsP, the nuclease nucA, the cyl operon which is responsible for hemolysin production and pigmentation as well as numerous effectors of type VII secretion. In addition, we recovered multiple hyper-pigmented/hemolytic GBS colonies from the murine diabetic wound environment which encode mutations in the two-component system covRS. We then go on to demonstrate that a mutant in cylE, which is repressed by CovR, is attenuated in diabetic wound infection. Finally, we examine the most highly upregulated gene pbsP in diabetic wound infection and find that PbsP is necessary for diabetic wound infection via adherence to the skin and promotion of inflammation.
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