Polymorphonuclear cells show features of dysfunctional activation during fatal sepsis
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ABSTRACT:
PROVIDER: PRJNA748037 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15193200.fastq.gz | Fastqsanger.gz | |||
| SRR15193201.fastq.gz | Fastqsanger.gz | |||
| SRR15193202.fastq.gz | Fastqsanger.gz | |||
| SRR15193203.fastq.gz | Fastqsanger.gz | |||
| SRR15193204.fastq.gz | Fastqsanger.gz |
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Project description:Sepsis and septic shock remain leading causes of morbidity and mortality for patients in Intensive care unit. In their early phase, immune cells produce various cytokines which lead to the prompt activation of the immune system. Polymorphonuclear leukocytes (PMNs) respond to different signals producing inflammatory factors and executing their antibacterial mechanisms, resulting in the engulfment and elimination of invading pathogens. However, long-term activation caused by various inflammatory signals produced during sepsis progression, can lead to the alteration of PMN signaling and subsequent defects in their functionality. Here we analyzed the PMNs samples from 34 patients in septic shock, we focused on PMNs gene expression and proteome changes caused by septic shock. We reveal that, compared to those of patients who survived, PMNs from patients who had a fulminant outcome were characterized by a dysfunctional hyper-activation, showing an altered metabolism, higher longevity and recent exit from cell cycle. We believe that this multi-omics approach, although limited, served to pinpoint the alterations in PMNs’ functionality, which may be reverted by targeted treatments.
2021-12-08 | GSE180387 | GEO
Project description:Sepsis and septic shock remain leading causes of morbidity and mortality for patients in the intensive care unit. During the early phase, immune cells produce various cytokines leading to prompt activation of the immune system. Polymorphonuclear leukocytes (PMNs) respond to different signals producing inflammatory factors and executing their antimicrobial mechanisms, resulting in the engulfment and elimination of invading pathogens. However, excessive activation caused by various inflammatory signals produced during sepsis progression can lead to the alteration of PMN signaling and subsequent defects in their functionality. Here, we analyzed samples from 34 patients in septic shock, focusing on PMNs gene expression and proteome changes associated with septic shock. We revealed that, compared to those patients who survived longer than five days, PMNs from patients who had fulminant sepsis were characterized by a dysfunctional hyper-activation, show altered metabolism, and recent exit from the cell cycle and signs of cellular lifespan. We believe that this multi-omics approach, although limited, pinpoints the alterations in PMNs' functionality, which may be rescued by targeted treatments.
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Project description:Systemic infections, especially in patients with chronic diseases, result in sepsis: an explosive, uncoordinated immune response that can lead to multisystem organ failure with a high mortality rate. Sepsis survivors and non-survivors oftentimes have similar clinical phenotypes or sepsis biomarker expression upon diagnosis, suggesting that the dynamics of sepsis in the critical early stage may have an impact on these opposite outcomes. To investigate this, we designed a within-subject study of patients with systemic gram-negative bacterial sepsis with surviving and fatal outcomes and performed single-cell transcriptomic analyses of peripheral blood mononuclear cells (PBMC) collected during the critical period between sepsis recognition and 6 hours. We observed that the largest sepsis-induced expression changes over time in surviving versus fatal sepsis were in CD14+ monocytes, including gene signatures previously reported for sepsis outcomes. We further identify changes in the metabolic pathways of both monocytes and platelets, the emergence of erythroid precursors, and T cell exhaustion signatures, with the most extreme differences occurring between the non-sepsis control and the sepsis non-survivor. Our single-cell observations are consistent with trends from public datasets but also reveal specific effects in individual immune cell populations, which change within hours. In conclusion, this pilot study provides the first single-cell results with a repeated measures design in sepsis to analyze the temporal changes in the immune cell population behavior in surviving or fatal sepsis. These findings indicate that tracking temporal expression changes in specific cell-types could lead to more accurate predictions of sepsis outcomes. We also identify molecular pathways that could be therapeutically controlled to improve the sepsis trajectory toward better outcomes.
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Project description:Dynamic changes in human single cell transcriptional signatures during fatal sepsis
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Project description:Extracellular ectonucleotidases are differentially regulated in murine tissues and human polymorphonuclear leukocytes during sepsis and inflammation
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Project description:With the successful implementation of guidelines from the Surviving Sepsis Campaign, in-hospital mortality to sepsis continues to decrease. However, this is has not lead to completely improved outcomes after sepsis. Up to 1/3 of sepsis survivors continue to have dismal long-term outcomes and 1-year mortality. Although the pathobiology of the dismal outcomes after sepsis remains undefined, it is thought that late after sepsis individuals enter a state of pathologic myeloid activation, inducing suboptimal lymphopoiesis and erythropoiesis, with many of the downstream immune cells being dysfunctional. The goal of this study was to use single-cell RNA sequencing to perform a detailed transcriptomic analysis of non-myeloid cells to better understand the pathology of late sepsis. Our findings highlight the unique transcriptomic pattern that circulating non-myeloid cells display 14 days after sepsis. Non-myeloid leukocytes in particular reveal an endotype of inflammation, immunosuppression and dysfunction. Immunomodulatory therapies at this late time point in sepsis may be feasible through precision medicine.
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Project description:This study tested the hypothesis that recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) enhances polymorphonuclear neutrophils (PMNs) via IL-1β to improve the prognosis of secondary infection in sepsis. The latter stage of sepsis is prone to induce immunosuppression, resulting in secondary fatal infections. rGM-CSF has become a way for sepsis-induced immunosuppression due to its immunomodulatory effect. However, the functional impact of GM-CSF on PMNs in sepsis remains obscure. This study aimed to study the role of rGM-CSF on the bactericidal ability of PMNs in septic mice, assessing its effect on the prognosis of secondary pneumonia, and explore the mechanism of rGM-CSF by intervening PMNs in patients with sepsis. The C57BL/6J sepsis mouse model was induced by cecal ligation and puncture (CLP). rmGM-CSF was used in vivo when mice developed immunosuppression, which was characterized by abnormal bactericidal function of PMNs in peripheral blood. rmGM-CSF improved the prognosis of secondary pneumonia and reversed the function of PMNs. PMNs isolated by Percoll from septic patients were treated by rhGM-CSF in vitro. The expression of CD11b, reactive oxygen species (ROS), phagocytosis and neutrophil extracellular traps (NETs) release in PMNs were enhanced by rhGM-CSF treatments. Whole-transcriptomic sequencing of mouse PMNs indicated that recombinant GM-CSF increased the expression of il1b gene in PMNs. Blocking and inhibiting IL-1β release effectively counteracted the enhancing effect of GM-CSF on the bactericidal function of PMNs. RmGM-CSF enhances the bactericidal function of PMNs in vivo and improves the prognosis of secondary pneumonia in septic mice, and recombinant GM-CSF increases IL-1β precursor reserves, which, if stimulated, can rapidly enhance the bactericidal capacity of PMNs.
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Project description:In the present studies we identified NTPDase8 a top downregulated gene in the liver of mice submitted to the cecal ligation-induced sepsis. Immunohistochemical analysis confirmed the decrease on NTPDase8 expression at the protein level. In vitro mechanistic studies using HepG2 hepatoma cells demonstrated that IL-6 but not TNF, IL-1b, bacteria or lipopolysaccharide are able to suppress NTPDase8 gene expression.
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Project description:The temporal evolution of sepsis was monitored by transcriptional profiling of five critically ill children with meningococcal sepsis and sepsis-induced multiple organ failure. Blood was sampled at 6 time points during the first 48 hours of their admission to pediatric intensive care, where the children received standard clinical treatment including organ support and antimicrobial therapy. Striking transcript instability was observed over the 48 hours, with increasing numbers of regulated genes over time. Most notably, proposed biomarkers for sepsis risk stratification also showed expression instability, with varied expression levels over 48 hours. This study demonstrates the extent of the complexity of temporal changes in gene expression that occur during the evolution of sepsis-induced multiple organ failure. Importantly, stratification tools that propose expression of biomarkers must take into account the temporal changes, over the use of single snapshots that may be less informative.
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