Linezolid Exerts Greater Bacterial Clearance but No Modification of Host Lung Gene Expression Profiling: a Mouse MRSA Pneumonia Model
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE46071 | GEO | 2014/04/10
SECONDARY ACCESSION(S): PRJNA200955
REPOSITORIES: GEO
Similar Datasets
Project description:Using the stringent criteria (fold change ≥ 1.5 up or down, P < 0.01, FDR < 0.05) to filter significantly differentially expressed genes, we did not identify any genes whose expression levels were significantly different between the PBS and PBS+LZD groups or between the LAC and LAC+LZD at Day 1 or Day 3 post MRSA infection. However, a remarkable difference was demonstrated (Figure 5A) between PBS and LAC groups at either Day 1 or Day 3 post MRSA infection. Four independent mouse lung tissue samples at Day 1 and Day 3 post MRSA infection with and without Linezolid therapy were randomly selected from each group for microarray analysis.
2014-04-10 | E-GEOD-46071 | biostudies-arrayexpress
Project description:Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging threat to human health throughout the world. Rodent MRSA pneumonia models mainly focus on the early innate immune responses to MRSA infection. However, the molecular pattern and mechanisms of recovery from MRSA lung infection are largely unknown. In this study, a nonlethal mouse MRSA pneumonia model was employed to investigate events during lung recovery from MRSA infection. We compared lung bacterial clearance, bronchoalveolar lavage fluid (BALF) characterization, lung histology, and gene expression profiling between Day 1 and Day 3 post-MRSA infection. Compared to Day 1 post-infection, bacterial colony counts and both BALF total cell number and protein concentration significantly decreased at Day 3 post-infection. Lung cDNA microarray analysis identified 47 significantly up-regulated and 35 down-regulated genes (p<0.01, 1.5-fold change [up and down]). Changes in eight genes were confirmed by real-time PCR. The pattern of gene expression suggests lung recovery is characterized by enhanced cell division, vascularization, and wound healing and by adjustment in host adaptive immune responses. Collectively, this data helps elucidate the molecular mechanisms of lung recovery after MRSA infection.
2013-11-12 | GSE36587 | GEO
Project description:Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging threat to human health throughout the world. Rodent MRSA pneumonia models mainly focus on the early innate immune responses to MRSA infection. However, the molecular pattern and mechanisms of recovery from MRSA lung infection are largely unknown. In this study, a nonlethal mouse MRSA pneumonia model was employed to investigate events during lung recovery from MRSA infection. We compared lung bacterial clearance, bronchoalveolar lavage fluid (BALF) characterization, lung histology, and gene expression profiling between Day 1 and Day 3 post-MRSA infection. Compared to Day 1 post-infection, bacterial colony counts and both BALF total cell number and protein concentration significantly decreased at Day 3 post-infection. Lung cDNA microarray analysis identified 47 significantly up-regulated and 35 down-regulated genes (p<0.01, 1.5-fold change [up and down]). Changes in eight genes were confirmed by real-time PCR. The pattern of gene expression suggests lung recovery is characterized by enhanced cell division, vascularization, and wound healing and by adjustment in host adaptive immune responses. Collectively, this data helps elucidate the molecular mechanisms of lung recovery after MRSA infection. RNA expression analysis was performed using the Illumina MouseRef-8 v2.0 BeadChip (Illumina, San Diego, CA), which provides coverage of approximately 25,700 genes and expressed sequence tags. Four independent mouse lung tissue samples at Day 1 and Day 3 post-MRSA infection were used in this study.
2013-11-12 | E-GEOD-36587 | biostudies-arrayexpress
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:The success of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) as pathogens is due to a combination of antibiotic resistance with high virulence. However, evolution of the exceptional virulence potential of CA-MRSA is not understood. Our previous study indicated that differential gene expression contributes substantially to this process. Thus, we here investigated the role of the pivotal virulence gene regulatory system agr in the most prevalent CA-MRSA strain USA300. Using a mouse subcutaneous infection model, we show that agr is essential for the development of CA-MRSA skin infections, the most frequent manifestation of disease caused by CA-MRSA. Furthermore, genome-wide analysis of gene expression revealed significant differences in agr-dependent virulence gene regulation between CA-MRSA, HA-MRSA, and laboratory strains. Our findings demonstrate that agr functionality is critical for CA-MRSA disease and indicate that an adaptation of the agr regulon to optimize expression of a broad set of virulence determinants may have contributed to the evolution of exceptionally pronounced virulence of CA-MRSA strains. Keywords: wild type vs mutant
2011-03-29 | GSE18793 | GEO
Project description:Influenza-induced respiratory failure is substantially worsened by secondary bacterial infections such as methicillin-resistant Staphylococcus aureus (MRSA). The bidirectional interaction between the influenza-injured lung microenvironment and MRSA is poorly understood. By conditioning MRSA ex vivo in bronchoalveolar lavage (BAL) fluid collected from mice at various timepoints of influenza infection, we found that influenza-injured lung microenvironment induces MRSA to increase cytotoxin expression while decreasing metabolic pathways. This overall increase in MRSA virulence was dependent upon SaeRS, a bacterial two-component system. Once expressed by MRSA, these influenza-induced toxins (such as Hla and LukAB) interact with host heparan sulfate (HS) fragments shed into the airspace. Highly-sulfated HS fragments augmented Hla- and LukAB-toxicity in vitro and in vivo. Our findings indicate that post-influenza MRSA pneumonia is shaped by bidirectional host-pathogen interactions: host injury triggers changes in bacterial expression of toxins, the activity of which are then shaped by host-derived HS fragments.
2022-11-29 | GSE199708 | GEO
Project description:The success of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) as pathogens is due to a combination of antibiotic resistance with high virulence. However, evolution of the exceptional virulence potential of CA-MRSA is not understood. Our previous study indicated that differential gene expression contributes substantially to this process. Thus, we here investigated the role of the pivotal virulence gene regulatory system agr in the most prevalent CA-MRSA strain USA300. Using a mouse subcutaneous infection model, we show that agr is essential for the development of CA-MRSA skin infections, the most frequent manifestation of disease caused by CA-MRSA. Furthermore, genome-wide analysis of gene expression revealed significant differences in agr-dependent virulence gene regulation between CA-MRSA, HA-MRSA, and laboratory strains. Our findings demonstrate that agr functionality is critical for CA-MRSA disease and indicate that an adaptation of the agr regulon to optimize expression of a broad set of virulence determinants may have contributed to the evolution of exceptionally pronounced virulence of CA-MRSA strains. Keywords: wild type vs mutant Wild type vs mutant agr strains.
2011-03-29 | E-GEOD-18793 | biostudies-arrayexpress
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:Methicillin-resistant Staphylococcus aureus (MRSA) is a major threat to human health. Rather than depend on creating new antibiotics (to which bacteria will eventually become resistant), we are employing antibiotic adjuvants that potentiate existing antibiotics. Based on our previous work, loratadine, the FDA-approvide antihistamine, effectively potentiates cell-wall active antibiotics in multiple strains of MRSA. Furthermore, loratadine and oxacillin helped disrupt preformed biofilms and stop them from initially forming in vitro. To gain biological insight into how this potentiation and biofilm inhibition occurs, we used RNA-seq on treated MRSA 43300 cultures to examine antibiotic adjuvant affects transcritome-wide.
2023-03-23 | GSE227099 | GEO
Project description:A strategy for the high-throughput screening of a peptide nucleic acid (PNA) encoded peptide library to allow the identification of MRSA and MSSA selective peptides including AMPs. This novel screening approach allows simultaneous screening of cell selective peptides with different uptake mechanisms including lytic peptides and non-lytic CPPs. MRSA and MSSA were incubated with Library-18 (50 uM; corresponding to 39 nM of each library member) under short incubation times (30 min) to ensure collection of both live and apoptotic cells, which allowed selection of lytic peptides as well as non-lytic CPPs. Incubation was followed by washing and lysis and the intracellular and membrane associated library members were extracted and purified by filter centrifugation (between 3,000 and 10,000 Da). The extracted PNA tags were hybridized onto custom designed microarrays. Each microarray consisted of 4 sub-arrays of 44,000 features each with 33 replicates of each oligonucleotide complementary to each member of the library as well as 1232 non-coding negative controls. Microarray scanning and data analysis (BlueFuse, BlueGenome) was used to extract the intensity of the FAM label, thereby giving the relative amount of PNA hybridized to each spot and the identity of the peptide.
2012-12-01 | E-MEXP-3327 | biostudies-arrayexpress