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PROVIDER: PRJNA831673 | ENA |
REPOSITORIES: ENA
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Project description:The precise mechanism and effects of antibiotics in host gene expression and immunomodulation in MRSA infection is unknown. Using a well characterized Methicillin Resistant Staphylococcus aureus (MRSA) isolate USA300 in a murine model of infection, we determined that linezolid and vancomycin induced differential production of bacterial toxins and host cytokines, differences in host gene expression, and differences in immunomodulators during MRSA bloodstream infection. A total of 35 A/J mice, categorized into seven groups (no infection; no infection with linezolid; no infection with vancomycin; 2 hour post-infection (hpi) S. aureus; 24 hpi S. aureus; 24 hpi S. aureus with linezolid; and 24 hpi S. aureus with vancomycin), were used in this study. Mice were injected with USA300 (6 x 106 CFU/g via i.p. route), then intravenously treated with linezolid (25 mg/kg) or vancomycin (25 mg/kg) at 2 hpi. Control and S. aureus infected mice were euthanized at each time point (2 h or 24h) following injection. Whole blood RNA was used for microarray; three cytokines and two S. aureus toxins [PantonValentine Leukocidin (PVL) and alpha hemolysin] were quantified in mouse serum by ELISA. S. aureus CFUs were significantly reduced in blood and kidney after linezolid or vancomycin treatment in S. aureus-infected mice. In vivo IL-1M-NM-2 in mouse serum was significantly reduced in both linezolid (p=0.001) and vancomycin (p=0.006) treated mice compared to untreated ones. IL-6 was significantly reduced only in linezolid treated (p<0.001) but not in vancomycin treated mice. However, another proinflammatory cytokine, TNF-M-NM-1, did not exhibit altered levels in either linezolid or vancomycin treated mice (p=0.3 and p=0.51 respectively). In vivo level of bacterial toxin, Panton-Valentine leukocidin, in mouse serum was significantly reduced only in linezolid treated mice (p=0.02) but not in vancomycin treated mice. There was no significant effect of either treatment in in vivo level of alpha hemolysin production. Unsupervised hierarchical clustering using the gene expression data from 35 microarrays revealed distinct clustering based on infection status and treatment group. Study of the antibiotic-specific difference in gene expression identified the number of genes uniquely expressed in response to S. aureus infection, infection with linezolid treatment, and infection with vancomycin treatment. Pathway associations study for the differentially expressed genes in each comparison group (Control vs. 24 h S. aureus infection, 24 h S. aureus infection vs. 24 h S. aureus linezolid, and 24 h S. aureus infection vs. 24 h S. aureus vancomycin) in mice using Kyoto Encyclopedia of Genes and Genomes (KEGG) identified toll-like receptor signaling pathway to be common to every comparison groups studied. Glycerolipid metabolism pathway was uniquely associated only with linezolid treatment comparison group. The findings of this study provide the evidence that protein synthesis inhibitor like linezolid does a better job in treating MRSA sepsis compared to cell wall acting antibiotics like vancomycin. To identify differences in host gene expression in a murine sepsis model treated with a) linezolid and b) vancomycin, we used whole blood gene expression (RNA) signatures from A/J inbred mice infected with USA 300 MRSA to evaluate differences in host gene expression among mice treated with linezolid and vancomycin. We used 5 RNA samples from MRSA-infected, linezolid- or vancomycin-treated mice. A total of 7 experimental groups have been employed: 1) Uninfected control group: (negative controls). 2) Uninfected, linezolid-treated group: Uninfected, linezolid-treated mice. 3) Uninfected vancomycin-treated group: Uninfected, vancomycin-treated mice. 4) Infected control group (positive control 2 h) MRSA-infected, untreated mice. 5) Infected control group (positive control 24 h): MRSA-infected, untreated mice. 6) Infected linezolid group: MRSA-infected, linezolid-treated mice. 7) Infected vancomycin group: MRSA-infected, vancomycin-treated mice.
2014-06-05 | E-GEOD-38531 | biostudies-arrayexpress
Project description:Purpose: Staphylococcus aureus is a highly successful human pathogen responsible for wide range of infections. In this study, we provide insights into the virulence, pathogenicity, and antimicrobial resistance determinants of methicillin susceptible and methicillin resistant Staphylococcus aureus (MSSA; MRSA) recovered from non-healthcare environments. Experiment design: Three environmental MSSA and three environmental MRSA were selected for proteomic profiling using iTRAQ MS/MS. Gene Ontology (GO) Annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Annotation were applied to interpret the functions of the proteins detected. Results: 792 proteins were identified in MSSA and MRSA. Comparative analysis of MRSA and MSSA revealed that 8 of out 792 proteins were up-regulated and 156 down-regulated. Differentially abundant proteins were predominantly involved in catalytic and binding activity. Among 164 proteins that had differences in abundance, 29 proteins were involved in pathogenesis, antimicrobial activities，stress response, mismatch repair and cell wall synthesis. Twenty-two proteins associated with pathogenicity, including spa, sbi, clfA and dlt were up-regulated in MRSA. Moreover, the up-regulated pathogenic protein entC2 in MSSA was determined to be a super antigen potentially capable of triggering toxic shock syndrome in the host. Conclusions: Enhanced pathogenicity, antimicrobial activity and stress response were observed in MRSA compared to MSSA.
2020-01-09 | PXD014478 | Pride
Project description:Staphylococcus aureus (S. aureus) is a gram-positive bacterium that causes a wide range of diseases. Terpinen-4-ol is a monoterpene component contained in most plant essential oils with good antibacterial activity. In this study, terpinen-4-ol effectively inhibited 13 strains of S. aureus, and effectively inhibited the biofilm of MRSA. Metabolomics and transcriptomics were used to elucidate changes in MRSA cells exposed to terpinen-4-ol. Terpinen-4-ol significantly changed (greater than a 2- or less than a 2-fold change) the expression of 304 genes and the level of 847 metabolites (greater than a 1.5- or less than a 0.67-fold change) in MRSA. The levels of genes and metabolites related to the valine, leucine and isoleucine biosynthesis metabolism pathway, the purine and pyrimidine metabolism pathway, energy metabolism and β-lactam resistance were dramatically changed in biofilms exposed to terpinen-4-ol. To the best of our knowledge, this research is the first to report the metabolite and expression profiles of MRSA exposed to terpinen-4-ol.
2020-09-09 | GSE157638 | GEO
Project description:Previous studies have documented the diversity of genetic background of methicillin-resistant S. aureus (MRSA) strains associated with healthcare (HA-MRSA), community (CA-MRSA) and livestock (LA-MRSA). The accessory and core-variable genome content of those strains remain largely unknown. To compare the composition of accessory and core-variable genome of Belgian MRSA strains according to host, population setting and genetic background, representative strains of HA- (n=21), CA- (n = 13) and ST398 LA-MRSA (n = 18) were characterized by a DNA-microarray (StaphVar Array) composed of oligonucleotide probes targeting ~400 resistance, adhesion and virulence associated genes.ST398 strains displayed very homogenous hybridization profiles (>94% gene content homology) irrespective of their host origin. This “ST398-specific” genomic profile was not distantly demarked from those of certain human-associated lineages but lacked several virulence- and colonization-associated genes harbored by strains of human origin, such as genes encoding proteases, haemolysins or adhesins. No enterotoxin gene was found among ST398 strains. In conclusion, our findings are consistent with a non-human origin of this ST398 lineage but suggest that it might have the potential to adapt further to the human host.
2010-11-15 | GSE20541 | GEO
Project description:Methicillin-resistant Staph. Aureus (MRSA) is a common cause of severe pneumonia and sepsis that can lead to Acute Respiratory Distress Syndrome (ARDS). MRSA causes lung endothelial cell (EC) dysfunction, a critical step in the pathogenesis and progression of lung injury. Our previous studies have demonstrated that FTY720 S-phosphonate (Tysiponate, Tys), an analog of sphingosine-1-phosphate, ameliorates MRSA-induced lung EC activation and barrier disruption (PMID: 35015568). To advance our mechanistic understanding of MRSA and Tys effects on lung EC, we investigated associated epigenetic changes. Specifically, we studied histone lysine acetylation, which is a central epigenetic alteration that has been linked to gene transcription and functional regulation of endothelial responses to inflammatory stimuli. We therefore determined the effects of MRSA exposure in the presence or absence of Tys on lung EC acetylation at the 9th lysine residue of the histone H3 protein (H3K9ac), which is an important chromatin modification associated with active promoters and gene activation. ChIP-seq analysis was employed to perform an unbiased genome-wide profiling of H3K9ac epigenetic patterns in human lung EC. This analysis identified multiple genes that are differentially targeted by acetylation when EC are exposed to MRSA±Tys.
2025-01-28 | GSE274958 | GEO