Massive Organ Inflammation in Experimental and in Clinical Meningococcal Septic Shock
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ORGANISM(S): Sus scrofa
PROVIDER: GSE198668 | GEO | 2022/03/17
REPOSITORIES: GEO
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Project description:Massive Organ Inflammation in Experimental and in Clinical Meningococcal Septic Shock
| PRJNA816427 | ENA
Project description:Meningococcal sepsis is an overwhelming form of the sepsis syndrome which may cause mortality within 12-24 hours in previously healthy children and adults, where the causative infectious agent is N. meningitidis, an obligate human pathogen. The genomic changes induced by N. meningitidis are modulated by the anti-inflammatory cytokine interleukin-10 (IL-10), which is present in large quantities in plasma from patients with meningococcal sepsis. This present study investigated kinase activities in human monocytes stimulated by N. meningitidis and IL-10. The first aim was to identify array peptides that could indicate which signaling pathways were activated or inhibited by the host response to the meningococci. The second aim was to detect whether IL-10 affected N. meningitidis-nduced phosphorylation of array peptides, in order to identify potential targets of the IL-10 anti-inflammatory response. We approached this using a strategy where elutriation-purified human monocytes are stimulated in vitro with N. meningitidis and IL-10, with concentrations corresponding to previously measured levels in patients with fulminant meningococcal septicemia. This work examined activation or inhibition of signaling pathways mediated by tyrosine kinases when purified human monocytes are in vitro incubated with N. meningitidis in the presence or absence of IL-10.
2017-12-15 | E-MTAB-4795 | biostudies-arrayexpress
Project description:Background: Biological interpretation of gene expression data may differ depending on underlying assumptions and statistical tests used by the chosen bioinformatic tool. We used Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) to analyze previously generated gene expression profiles induced in human monocytes by N. meningitidis and IL-10 (“the model system”), and by meningococcal sepsis plasma before and after immunodepletion of IL-10 (“the patient plasma system”). The objectives were to compare whether these two methods resulted in similar biological interpretation of the datasets; and identify whether GSEA provided additional insight about the human monocyte host response to meningococcal activation. Results: In both experimental models, GSEA and IPA associated genes induced in monocytes by N. meningitidis with pro-inflammatory innate immune activation, including TNF-signaling, Toll-like receptor signaling, JAK-STAT-signaling, type I and type II interferon. GSEA associated genes regulated by the presence of IL-10 with similar gene sets in both the model system and the patient plasma system. In the model system, GSEA and IPA identified 170 genes associated with oxidative phosphorylation/mitochondrial function to be down-regulated in monocytes stimulated with meningococci. In the patient plasma system, GSEA and IPA combined identified 122 genes associated with oxidative phosphorylation/mitochondrial dysfunction to be down-regulated by meningococcal sepsis plasma depleted for IL-10. Combining analyses from GSEA and IPA identified that some genes associated with oxidative phosphorylation/mitochondrial function that were inhibited by N. meningitidis were partially up-regulated by IL-10. Conclusions: Biological processes associated with the gene expression changes in the model system of meningococcal sepsis was comparable to the results found in the patient plasma system. By combining GSEA with IPA, we have discovered an inhibitory effect exerted by N. meningitidis on genes associated with oxidative phosphorylation, and that IL-10 possibly partially dampen this strong inhibitory effect, thereby identifying, to our knowledge, yet another area where IL-10 regulates the effect of LPS. We suggest that relying on a single bioinformatic tool together with arbitrarily chosen filtering criteria for data analysis may result in overlooking relevant biological processes and signaling pathways associated with genes differentially expressed between compared experimental conditions.
2016-06-08 | GSE82315 | GEO
Project description:Background: Biological interpretation of gene expression data may differ depending on underlying assumptions and statistical tests used by the chosen bioinformatic tool. We used Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) to analyze previously generated gene expression profiles induced in human monocytes by N. meningitidis and IL-10 (“the model system”), and by meningococcal sepsis plasma before and after immunodepletion of IL-10 (“the patient plasma system”). The objectives were to compare whether these two methods resulted in similar biological interpretation of the datasets; and identify whether GSEA provided additional insight about the human monocyte host response to meningococcal activation. Results: In both experimental models, GSEA and IPA associated genes induced in monocytes by N. meningitidis with pro-inflammatory innate immune activation, including TNF-signaling, Toll-like receptor signaling, JAK-STAT-signaling, type I and type II interferon. GSEA associated genes regulated by the presence of IL-10 with similar gene sets in both the model system and the patient plasma system. In the model system, GSEA and IPA identified 170 genes associated with oxidative phosphorylation/mitochondrial function to be down-regulated in monocytes stimulated with meningococci. In the patient plasma system, GSEA and IPA combined identified 122 genes associated with oxidative phosphorylation/mitochondrial dysfunction to be down-regulated by meningococcal sepsis plasma depleted for IL-10. Combining analyses from GSEA and IPA identified that some genes associated with oxidative phosphorylation/mitochondrial function that were inhibited by N. meningitidis were partially up-regulated by IL-10. Conclusions: Biological processes associated with the gene expression changes in the model system of meningococcal sepsis was comparable to the results found in the patient plasma system. By combining GSEA with IPA, we have discovered an inhibitory effect exerted by N. meningitidis on genes associated with oxidative phosphorylation, and that IL-10 possibly partially dampen this strong inhibitory effect, thereby identifying, to our knowledge, yet another area where IL-10 regulates the effect of LPS. We suggest that relying on a single bioinformatic tool together with arbitrarily chosen filtering criteria for data analysis may result in overlooking relevant biological processes and signaling pathways associated with genes differentially expressed between compared experimental conditions.
2016-06-08 | GSE82166 | GEO
Project description:Objective. Meningococcal sepsis remains an important cause of childhood morbidity and mortality. Largely due to logistic complexities of research in young children with acute life-threatening disease, very little is known regarding differential expression kinetics and molecular regulation of immune response genes in leukocyte subsets. Materials and methods. In this prospective case-control study, six children with meningococcal sepsis were included. Blood was drawn at four time points (t=0, t=8, t=24 and t=72 h after admission to the paediatric intensive care unit). Blood was also collected from matched controls. Detailed immunophenotyping of leukocytes was performed; RNA isolated from whole blood, lymphocytes, monocytes, and granulocytes was used to perform Affymetrix micro-array gene expression analysis. Results and conclusion. There were no differences in total leukocyte count between patients and controls. In contrast to previous in vitro studies we observed an unexpected decrease in NK cell numbers, as well as downregulation of NK cell specific and cytotoxic T-cell related gene expression in patients with meningococcal septic shock. By contrast, expression of genes, involved in innate immunity and several other pathways, differed between the different leukocyte subpopulations in a dynamic fashion. Compared to previously reported gene expression profiles, it was possible to define a meningococcal sepsis specific expression profile.
2008-06-14 | GSE11755 | GEO
Project description:Background: Patients developing meningococcal septic shock reveal very high levels of Neisseira meningitidis and endotoxin in the circulation and organs, leading to acute cardiovascular, pulmonary and renal failure, coagulopathy and a high case fatality rate within 24 hours. Objective: To investigate transcriptional profiles in heart, lungs, kidneys, liver and spleen and immunostain key inflammatory cells and proteins in post mortem formalin-fixed, paraffin-embedded (FFPE) tissue samples from meningococcal septic shock patients. Patients and methods: Total RNA was isolated from FFPE and fresh frozen (FF) tissue samples from five patients and two controls (non-inflammatory disease). Differential expression of genes was detected using Affymetrix GeneChip Human Transcriptome 2.0 Arrays. Lung and heart tissue samples were immunostained for T-and B cells, macrophages, neutrophils and the inflammatory markers Plasminogen activator inhibitor-1 (PAI-1) and Monocyte chemoattractant protein 1 (MCP-1). Inflammatory mediators were quantified in lysates from FF tissues. Results: The transcriptional profiles showed significant regulation of pathways associated with organismal death, cell death and survival, leukocyte migration, cellular movement, proliferation of cells, cell-to-cell signaling, immune cell trafficking and inflammatory responses in an organ-specific clustering manner. The canonical pathways including acute phase response-, EIF2-, TREM1-, IL-6-, HMBG1-, PPAR signaling and LXR/RXR activation were associated with acute heart, pulmonary and renal failure and with inflammatory changes in liver and spleen were identified. The main upstream regulators were TNF, IL-1β, IL-6, RICTOR, miR-6739-3p and CD3. Increased numbers of inflammatory cells (CD68+, MPO+, CD3+ and CD20+) were found in lungs and heart. PAI-1 inhibiting fibrinolysis and MCP-1 attracting leukocyte were found significantly present in the septic tissue samples compared to the controls. Conclusions: Hundreds of transcripts were altered in lungs, heart and kidneys, all organs with an acute dysfunction. Relatively fewer transcripts were changed in the spleen. Certain transcripts were associated with the number of. N. meningitidis in the tissues. We identified specific biomarker panels which differed from organ to organ. Our results highlight the complexity of gene regulation in the different tissues. Future treatment strategies blocking or stimulating only one molecule or pathway appear unlikely to succeed.
2020-01-14 | GSE141864 | GEO
Project description:Neisseria meningitidis, a commensal β-proteobacterium of the human nasopharynx, constitutes a worldwide leading cause of sepsis and epidemic meningitis. The molecular basis for their "accidental" pathogenicity is still not fully understood. Here, we show that knock-out strains lacking the Cas9 protein are impaired in the adhesion to human nasopharyngeal cells which constitutes a central step in the pathogenesis of invasive meningococcal disease. Transcriptome sequencing data suggest that meningococcal Cas9 does not affect the expression of classical surface adhesins but rather exerts its effect on cell adhesion in an indirect manner. Consequently, we speculate that the meningococcal type II-C CRISPR/Cas system exerts novel functions beyond its established role in defence against foreign DNA.
2018-05-01 | GSE110891 | GEO
Project description:The rapid development in septic patients of features of marked immunosuppression associated with increased risk of nosocomial infections and mortality represents the rational for the initiation of immune targeted treatments in sepsis. However, as there is no clinical sign of immune dysfunctions, the current challenge is to develop biomarkers that will help clinicians identify the patients that would benefit from immunotherapy and monitor its efficacy. Using an in vitro model of endotoxin tolerance (ET), a pivotal feature of sepsis-induced immunosuppression in monocytes, we identified using gene expression profiling by microarray a panel of transcripts associated with the development of ET which expression was restored after immunostimulation with interferon-gamma (IFN-M-NM-3). These results were confirmed by qRT-PCR. Importantly, this short-list of markers was further evaluated in patients. Of these transcripts, six (TNFAIP6, FCN1, CXCL10, GBP1, CXCL5 and PID1) were differentially expressed in septic shock patientsM-bM-^@M-^Y blood compared to healthy blood upon ex vivo LPS stimulation and were restored by IFN-M-NM-3. In this study, by combining a microarray approach in an in vitro model and a validation in clinical samples, we identified a panel of six transcripts that could be used for the identification of septic patients eligible for IFNg therapy. The potential value of these markers should now be evaluated in a larger cohort of patients. Upon favorable results, they could serve as stratification tools prior to immunostimulatory treatment and to monitor drug efficacy. PBMCs from 6 healthy donor were left unstimulated (medium) or with 1 shot of LPS (LPS unprimed), 2 shots of LPS (LPS primed) or 2 shots of LPS and Interferon gamma (LPS primed + IFNg).
2013-07-31 | E-GEOD-46914 | biostudies-arrayexpress
Project description:Objective. Meningococcal sepsis remains an important cause of childhood morbidity and mortality. Largely due to logistic complexities of research in young children with acute life-threatening disease, very little is known regarding differential expression kinetics and molecular regulation of immune response genes in leukocyte subsets. Materials and methods. In this prospective case-control study, six children with meningococcal sepsis were included. Blood was drawn at four time points (t=0, t=8, t=24 and t=72 h after admission to the paediatric intensive care unit). Blood was also collected from matched controls. Detailed immunophenotyping of leukocytes was performed; RNA isolated from whole blood, lymphocytes, monocytes, and granulocytes was used to perform Affymetrix micro-array gene expression analysis. Results and conclusion. There were no differences in total leukocyte count between patients and controls. In contrast to previous in vitro studies we observed an unexpected decrease in NK cell numbers, as well as downregulation of NK cell specific and cytotoxic T-cell related gene expression in patients with meningococcal septic shock. By contrast, expression of genes, involved in innate immunity and several other pathways, differed between the different leukocyte subpopulations in a dynamic fashion. Compared to previously reported gene expression profiles, it was possible to define a meningococcal sepsis specific expression profile. Experiment Overall Design: In this prospective case-control study, six children with meningococcal sepsis were included. Blood was drawn at four time points (t=0, t=8, t=24 and t=72 h after admission to the paediatric intensive care unit). Blood was also collected from matched controls. Detailed immunophenotyping of leukocytes was performed; RNA isolated from whole blood, lymphocytes, monocytes, and granulocytes was used to perform Affymetrix micro-array gene expression analysis. Experiment Overall Design: No replicates were performed. Experiment Overall Design: Table 4. Results of between-subject analyses. Experiment Overall Design: Source Time (h) ca co/ca at t=T Experiment Overall Design: Blood t0: ca:2 3, co: a b c; t8: 2; t24 :ca:1 2 3; t72: ca:1 2. Experiment Overall Design: Lym t0: ca:2 3, co:a b c d;t8: ca:1 3 4;t24: ca:1 2 3 4 6; t72: ca: 1 2. Experiment Overall Design: Mono t0:ca: 1 3 4 6, co: a b d; t8: ca:1 2 3; t24:ca: 1 2 3; t72: ca:1. Experiment Overall Design: Numbers represent the patient identification numbers. Experiment Overall Design: Characters represent the individual controls.
2008-10-21 | E-GEOD-11755 | biostudies-arrayexpress
Project description:Group ACYW135 meningococcal polysaccharide vaccine (MPV-ACYW135) is a classical common vaccine used to prevent Neisseria meningitidis serogroup A, C, Y, W135. Although immunological research on MPV has been relatively complete in the past few decades, studies on the vaccine at the transcriptional levels are still limited. In the present study, mRNAs and lncRNAs related to immunity were screened from spleens of mice inoculated with MPV-ACYW135 and compared with the control group to identify the effect and mechanism of these mRNAs and lncRNAs on the immune response. A comprehensive analysis of mRNAs and lncRNAs between MPV group and control group was performed by RNA-seq with bioinformatics.
2023-08-30 | GSE224584 | GEO