Septic Shock in Advanced Age: Transcriptome Analysis Reveals Altered Molecular Signatures in Neutrophil Granulocytes.
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SUBMITTER: Vieira da Silva Pellegrina D
PROVIDER: S-EPMC4457834 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Transcriptional profiling of granulocytes from 24 subjects was used to investigate their differences regarding sepsis and aging. Two-colour hybridization design. Aliquots of total RNA isolated from adult or elder individuals with sepsis or healthy controls were labeled with Cy3 and co-hybridized with a common reference RNA pool (Universal Human Reference RNA, Agilent, cat #740000) labeled with Cy5 . Biological replicates:6 per group. No technical replicates.
2015-06-10 | E-GEOD-67652 | biostudies-arrayexpress
Project description:Transcriptional profiling of granulocytes from 24 subjects was used to investigate their differences regarding sepsis and aging.
2015-06-10 | GSE67652 | GEO
Project description:Neutrophil granulocytes are the first defense line in bacterial infections. However, granulocytes are also responsible for severe local tissue impairment. In order to use donor granulocytes, but at the same time to avoid local side effects, we developed an extracorporeal immune support system. This first-in-man study investigated whether an extracorporeal plasma treatment with a granulocyte bioreactor is tolerable in patients with septic shock. A further intention was to find suitable efficacy end-points for subsequent controlled trials.The trial was conducted as a prospective uncontrolled clinical phase I/II study with 28-day follow-up at three university hospital intensive care units. Ten consecutive patients (five men, five women, mean age 60.3 ± 13.9 standard deviation (SD) years) with septic shock with mean ICU entrance scores of Acute Physiology and Chronic Health Evaluation (APACHE) II of 29.9 ± 7.2 and of Simplified Acute Physiology Score (SAPS) II of 66.2 ± 19.5 were treated twice within 72 hours for a mean of 342 ± 64 minutes/treatment with an extracorporeal bioreactor containing 1.41 ± 0.43 × 10E10 granulocytes from healthy donors. On average, 9.8 ± 2.3 liters separated plasma were treated by the therapeutic donor cells. Patients were followed up for 28 days.Tolerance and technical safety during treatment, single organ functions pre/post treatment, and hospital survival were monitored. The extracorporeal treatments were well tolerated. During the treatments, the bacterial endotoxin concentration showed significant reduction. Furthermore, noradrenaline dosage could be significantly reduced while mean arterial pressure was stable. Also, C-reactive protein, procalcitonin, and human leukocyte antigen DR (HLA-DR) showed significant improvement. Four patients died in the hospital on days 6, 9, 18 and 40. Six patients could be discharged.The extracorporeal treatment with donor granulocytes appeared to be well tolerated and showed promising efficacy results, encouraging further studies.ClinicalTrials.gov Identifier: NCT00818597.
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Project description:Septic shock by pneumopathy was studied in prospective way in 20 patients and compared to normal blood. Blood samples were taken within 12 hours of diagnosis and the resulting transcritomes were compared to 42 normal control samples (selected samples from series GSE10715, GSE12711, GSE16728 and GSE7400). keywords: patient cohort study, septic shock, transcription-profile, blood
2017-09-08 | GSE33118 | GEO
Project description:BACKGROUND:Platelets have been demonstrated to be potent activators of neutrophil extracellular trap (NET) formation during sepsis. However, the mediators and molecular pathways involved in human platelet-mediated NET generation remain poorly defined. Circulating plasma exosomes mostly originating from platelets may induce vascular apoptosis and myocardial dysfunction during sepsis; however, their role in NET formation remains unclear. This study aimed to detect whether platelet-derived exosomes could promote NET formation during septic shock and determine the potential mechanisms involved. METHODS:Polymorphonuclear neutrophils (PMNs) were cocultured with exosomes isolated from the plasma of healthy controls and septic shock patients or the supernatant of human platelets stimulated ex vivo with phosphate buffer saline (PBS) or lipopolysaccharide (LPS). A lethal cecal ligation and puncture (CLP) mouse model was used to mimic sepsis in vivo; then, NET formation and molecular pathways were detected. RESULTS:NET components (dsDNA and MPO-DNA complexes) were significantly increased in response to treatment with septic shock patient-derived exosomes and correlated positively with disease severity and outcome. In the animal CLP model, platelet depletion reduced plasma exosome concentration, NET formation, and lung injury. Mechanistic studies demonstrated that exosomal high-mobility group protein 1 (HMGB1) and/or miR-15b-5p and miR-378a-3p induced NET formation through the Akt/mTOR autophagy pathway. Furthermore, the results suggested that I?B kinase (IKK) controls platelet-derived exosome secretion in septic shock. CONCLUSIONS:Platelet-derived exosomes promote excessive NET formation in sepsis and subsequent organ injury. This finding suggests a previously unidentified role of platelet-derived exosomes in sepsis and may lead to new therapeutic approaches.
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Project description:BACKGROUND:Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Numerous studies have explored the complex and dynamic transcriptome modulations observed in sepsis patients, but a large fraction of the transcriptome remains unexplored. This fraction could provide information to better understand sepsis pathophysiology. Multiple levels of interaction between human endogenous retroviruses (HERV) and the immune response have led us to hypothesize that sepsis is associated with HERV transcription and that HERVs may contribute to a signature among septic patients allowing stratification and personalized management. METHODS:We used a high-density microarray and RT-qPCR to evaluate the HERV and Mammalian Apparent Long Terminal Repeat retrotransposons (MaLR) transcriptome in a pilot study that included 20 selected septic shock patients, stratified on mHLA-DR expression, with samples collected on day 1 and day 3 after inclusion. We validated the results in an unselected, independent cohort that included 100 septic shock patients on day 3 after inclusion. We compared septic shock patients, according to their immune status, to describe the transcriptional HERV/MaLR and conventional gene expression. For differential expression analyses, moderated t tests were performed and Wilcoxon signed-rank tests were used to analyze RT-qPCR results. RESULTS:We showed that 6.9% of the HERV/MaLR repertoire was transcribed in the whole blood, and septic shock was associated with an early modulation of a few thousand of these loci, in comparison to healthy volunteers. We provided evidence that a subset of HERV/MaLR and conventional genes were differentially expressed in septic shock patients, according to their immune status, using monocyte HLA-DR (mHLA-DR) expression as a proxy. A group of 193 differentially expressed HERV/MaLR probesets, tested in an independent septic shock cohort, identified two groups of patients with different immune status and severity features. CONCLUSION:We demonstrated that a large, unexplored part of our genome, which codes for HERV/MaLR, may be linked to the host immune response. The identified set of HERV/MaLR probesets should be evaluated on a large scale to assess the relevance of these loci in the stratification of septic shock patients. This may help to address the heterogeneity of these patients.
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Project description:Timely and reliable distinction of non-infectious systemic inflammatory response syndrome (SIRS), common in critically ill patients, from sepsis to support adequate antimicrobial therapy safes lives but is clinically challenging. Expeditious sepsis biomarkers are thus urgently sought. Blood transcriptional profiling provides insights into sepsis pathophysiology, but variability in leukocyte subtype composition complicates profile interpretation, and reliable reference genes to normalize gene expression in sepsis are lacking. Here, we identified AKIRIN1 as a reference gene, specifically, in peripheral NK cells and granulocytes for differential gene expression analysis between patients with SIRS and septic shock on intensive care unit admission. Discovery by a two-step probabilistic selection from microarray data followed by validation through branched DNA assays in independent patients revealed several candidate reference genes in NK cells, namely, AKIRIN1, PPP6R3, TAX1BP1, and ADRBK1. For in vitro priming of NK cells, GUSB however was confirmed as reference gene of choice. Initially, no candidate genes could be validated in granulocytes, an additional rescreen of known reference genes by RT-PCR included. By serendipity, we could determine equal AKIRIN1 expression levels also in SIRS and septic shock granulocytes and no change by in vitro challenge of granulocytes with LPS. Inspection of four external neutrophil transcriptome datasets further support unchanged AKIRIN1 expression in human systemic inflammation. Invariable AKIRIN1 expression in peripheral NK cells and granulocytes needs further validation in sepsis and other infectious and inflammatory diseases. As a reference gene in these cells and conditions, AKIRIN1 may further our understanding of innate immunity and lead to new biomarkers.
2019-06-10 | GSE123729 | GEO
Project description:Neutrophils are required for host resistance against Streptococcus pneumoniae, but their function declines with age. We previously found that CD73, an enzyme required for antimicrobial activity, is downregulated in neutrophils (also known as polymorphonuclear leukocytes [PMNs]) from aged mice. This study explored transcriptional changes in neutrophils induced by S. pneumoniae to identify pathways controlled by CD73 and dysregulated with age. Pure bone marrow-derived neutrophils isolated from wild-type (WT) young and old and CD73 knockout (CD73KO) young mice were mock challenged or infected with S. pneumoniae ex vivo. RNA sequencing (RNA-Seq) was performed to identify differentially expressed genes (DEGs). We found that infection triggered distinct global transcriptional changes across hosts that were strongest in CD73KO neutrophils. Surprisingly, there were more downregulated than upregulated genes in all groups upon infection. Downregulated DEGs indicated a dampening of immune responses in old and CD73KO hosts. Further analysis revealed that CD73KO neutrophils expressed higher numbers of long noncoding RNAs (lncRNAs) than those in WT controls. Predicted network analysis indicated that CD73KO-specific lncRNAs control several signaling pathways. We found that genes in the c-Jun N-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) pathway were upregulated upon infection in CD73KO mice and in WT old mice, but not in WT young mice. This corresponded to functional differences, as phosphorylation of the downstream AP-1 transcription factor component c-Jun was significantly higher in neutrophils from infected CD73KO mice and old mice. Importantly, inhibition of JNK/AP-1 rescued the ability of these neutrophils to kill S. pneumoniae. Together, our findings revealed that the ability of neutrophils to modify their gene expression to better adapt to bacterial infection is in part regulated by CD73 and declines with age.
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Project description:Septic shock as a subset of sepsis, has a much higher mortality, while the mechanism is still elusive. This study was aimed at identifying core mechanisms associated with septic shock and its high mortality by investigating transcriptome data. We screened 72 septic-shock-associated genes (SSAGs) with differential expression between septic shock and sepsis in the discovery dataset. Further gene set enrichment analysis identified upregulated neutrophil activation and impaired T-cell activation in septic shock. Co-expression analysis revealed nine co-expressed gene modules. In addition, we determined twenty-one prognostic SSAGs using cox regression analysis in an independent dataset. Moreover, protein-protein interaction (PPI) network revealed two clusters. Among these neutrophil activation was enriched in the most positively-related modules and the cluster2 PPI network, while T-cell activation was enriched in both the most negatively-related module and one of the most positively-related modules as well as the cluster1 PPI network. ELANE, LCN2 and IFI44 were identified as hub genes with CytoHubba methods and semantic similarity analysis. Notably, ELANE was the only prognostic gene and was further validated in an external dataset. Blood neutrophil count was demonstrated to increase in septic shock and be a risky factor of prognosis based on clinical data. In conclusions, septic shock is associated with upregulated neutrophil activation and dysregulated T-cell activation. Three hub genes might have potentials as sensitive markers for the further translational research and ELANE could be a robust prognostic biomarker and effective therapeutic target.
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Project description:Heterogeneity in sepsis-related pathobiology presents a significant challenge. Resolving this heterogeneity presents an opportunity to understand pathobiology and improve patient care. Olfactomedin-4 is a neutrophil subset marker and may contribute to sepsis heterogeneity. Our objective was to evaluate the expression of olfactomedin-4 and characterize neutrophil heterogeneity in children with septic shock.Single-center, prospective cohort, as well as secondary analysis of existing transcriptomic and proteomic databases.Tertiary care PICU.Patients from 5 days to 18 years old with septic shock were enrolled. Data collected included the expression of olfactomedin-4 messenger RNA, serum protein concentrations, and percentage of neutrophils that express olfactomedin-4.None.Secondary analysis of existing transcriptomic data demonstrated that olfactomedin-4 is the most highly expressed gene in nonsurvivors of pediatric septic shock, compared with survivors. Secondary analysis of an existing proteomic database corroborated these observations. In a prospectively enrolled cohort, we quantified the percentage of olfactomedin-4+ neutrophils in patients with septic shock. Patients with a complicated course, defined as greater than or equal to two organ failures at day 7 of septic shock or 28-day mortality, had a higher percentage of olfactomedin-4+ neutrophils, compared with those without a complicated course. By logistic regression, the percentage of olfactomedin-4+ neutrophils was independently associated with increased risk of a complicated course (odds ratio, 1.09; 95% CI, 1.01-1.17; p = 0.024).Olfactomedin-4 identifies a subpopulation of neutrophils in patients with septic shock, and those with a high percentage of olfactomedin-4+ neutrophils are at higher risk for greater organ failure burden and death. Olfactomedin-4 might serve as a marker of a pathogenic neutrophil subset in patients with septic shock.
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