Dynamic changes in human single cell transcriptional signatures during fatal sepsis
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ABSTRACT:
PROVIDER: PRJNA704394 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13772206_1.fastq.gz | Fastqsanger.gz | |||
| SRR13772206_2.fastq.gz | Fastqsanger.gz | |||
| SRR13772207_1.fastq.gz | Fastqsanger.gz | |||
| SRR13772207_2.fastq.gz | Fastqsanger.gz | |||
| SRR13772208_1.fastq.gz | Fastqsanger.gz |
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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.
2021-03-03 | GSE167363 | GEO
Project description:Systemic infections, especially in patients with chronic diseases, may result in sepsis: an explosive, uncoordinated immune response that can lead to multisystem organ failure with a high mortality rate. Patients with similar clinical phenotypes or sepsis biomarker expression upon diagnosis may have different outcomes, suggesting that the dynamics of sepsis is critical in disease progression. A within-subject study of patients with Gram-negative bacterial sepsis with surviving and fatal outcomes was designed and single-cell transcriptomic analyses of peripheral blood mononuclear cells (PBMC) collected during the critical period between sepsis diagnosis and 6 h were performed. The single-cell observations in the study are consistent with trends from public datasets but also identify dynamic effects in individual cell subsets that change within hours. It is shown that platelet and erythroid precursor responses are drivers of fatal sepsis, with transcriptional signatures that are shared with severe COVID-19 disease. It is also shown that hypoxic stress is a driving factor in immune and metabolic dysfunction of monocytes and erythroid precursors. Last, the data support CD52 as a prognostic biomarker and therapeutic target for sepsis as its expression dynamically increases in lymphocytes and correlates with improved sepsis outcomes. In conclusion, this study describes the first single-cell study that analyzed short-term temporal changes in the immune cell populations and their characteristics in surviving or fatal sepsis. Tracking temporal expression changes in specific cell types could lead to more accurate predictions of sepsis outcomes and identify molecular biomarkers and pathways that could be therapeutically controlled to improve the sepsis trajectory toward better outcomes.
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Project description:Polymorphonuclear cells show features of dysfunctional activation during fatal sepsis
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Project description:Severely-afflicted COVID-19 patients can exhibit disease manifestations representative of sepsis, including acute respiratory distress syndrome and multiple organ failure. We hypothesized that diagnostic tools used in managing all-cause sepsis, such as clinical criteria, biomarkers, and gene expression signatures, should extend to COVID-19 patients. Here we analyzed the whole blood transcriptome of 124 early (1-5 days post-hospital admission) and late (6-20 days post-admission) sampled patients with confirmed COVID-19 infections from hospitals in Quebec, Canada. Mechanisms associated with COVID-19 severity were identified between severity groups (ranging from mild disease to the requirement for mechanical ventilation and mortality), and established sepsis signatures were assessed for dysregulation. Specifically, gene expression signatures representing pathophysiological events, namely cellular reprogramming, organ dysfunction, and mortality, were significantly enriched and predictive of severity and lethality in COVID-19 patients. Mechanistic endotypes reflective of distinct sepsis aetiologies and therapeutic opportunities were also identified in subsets of patients, enabling prediction of potentially-effective repurposed drugs. The expression of sepsis gene expression signatures in severely-afflicted COVID-19 patients indicates that these patients should be classified as having severe sepsis. Accordingly, in severe COVID-19 patients, these signatures should be strongly considered for the mechanistic characterization, diagnosis, and guidance of treatment using repurposed drugs.
2022-12-18 | GSE221234 | GEO
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:Single-cell transcriptomic changes in sepsis patient
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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: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:Identifying immune signatures of sepsis in very preterm babies
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Project description:Identifying at first clinical presentation gene expression signatures that predict subsequent severity will allow clinicians to identify the most at risk groups of patients, and also enable appropriate antibiotic use. Accordingly, we characterized the blood immune profiles of patients with early/pre-sepsis to identify signatures reflecting disease severity, organ dysfunction, mortality, and specific endotypes/mechanisms.
2022-01-10 | GSE185263 | GEO