A Novel Single Cell RNA-seq Analysis of Circulating Immune Cells in Late Sepsis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE175453 | GEO | 2021/06/04
REPOSITORIES: GEO
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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:The aim of the experiment was to assign patients enrolled in the VANISH randomised trial to sepsis response signature (SRS) endotypes based on a previously published gene expression signature, in order to test for differential responses to treatment. VANISH was a double-blind randomised clinical trial in septic shock, with patients randomised to receive norepinephrine or vasopressin followed by hydrocortisone or placebo. We collected blood samples upon enrolment, extracted RNA and performed transcriptomic profiling using microarrays, allocated patients to SRS1 or SRS2 using a linear model (Davenport 2016), and tested for an association between sepsis endotype and response to either norepinephrine or vasopressin, or to corticosteroids. There was a significant interaction between treatment with hydrocortisone or placebo, and SRS endotype (p=0·02)
2022-07-12 | E-MTAB-7581 | biostudies-arrayexpress
Project description:Background: Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality. Results: The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (infection with SIRS), including 78 sepsis survivors and 28 sepsis nonsurvivors, who had previously undergone plasma proteomic and metabolomic profiling. The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflective of immune activation in sepsis. The expression of 1,238 genes differed with sepsis outcome: Nonsurvivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease â rare variant hypothesis. VPS9D1, whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors, and these were associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology. Conclusions: Host response in sepsis survivors â activation of immune response-related genes â was muted in sepsis nonsurvivors. The association of sepsis survival with robust immune response and presence of missense variants in VPS9D1 warrants replication and further functional studies. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS, n=23) or sepsis (infection with SIRS), including 78 sepsis survivors and 28 sepsis nonsurvivors, who had previously undergone plasma proteomic and metabolomic profiling.
2015-01-01 | E-GEOD-63042 | biostudies-arrayexpress
Project description:The maladaptive response to infection leading to the clinical syndrome of sepsis is highly heterogeneous, confounding immunotherapy trials. Here we establish the pathophysiology of a sepsis response endotype informative for immune state, disease severity, outcome and therapy. We applied whole blood single-cell multiomics (272,993 cells, n=39 individuals) and found patients with this endotype had increased IL1R2+ immature neutrophils, confirmed using CyTOF (n=41 samples) and RNA-sequencing (n=677 individuals), and upregulated STAT3 programs with plasma cytokine profiles of emergency granulopoiesis (EG). We characterised sepsis hematopoietic stem cells (29,336 cells, n=27 samples) with multiomics, and demonstrated endotype-specific EG transcriptional skewing together with STAT3 and EG master regulator CEBPB epigenetic signatures. Our findings establish an immunohematopoietic basis for a deleterious sepsis endotype and nominate IL-6/G-CSF as potential therapeutic targets.
| EGAS00001006283 | EGA
Project description:Background: Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality. Results: The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (infection with SIRS), including 78 sepsis survivors and 28 sepsis nonsurvivors, who had previously undergone plasma proteomic and metabolomic profiling. The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflective of immune activation in sepsis. The expression of 1,238 genes differed with sepsis outcome: Nonsurvivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease – rare variant hypothesis. VPS9D1, whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors, and these were associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology. Conclusions: Host response in sepsis survivors – activation of immune response-related genes – was muted in sepsis nonsurvivors. The association of sepsis survival with robust immune response and presence of missense variants in VPS9D1 warrants replication and further functional studies.
2015-01-01 | GSE63042 | GEO
Project description:The mortality risk from cancer-associated sepsis is differentially affected by individual cancer sites and host responses to sepsis are heterogenous. Native Hawaiians have a 2-fold higher mortality risk from cancer-associated sepsis than Whites and also higher mortality risk from colorectal cancer (CRC). We investigated this disparity by examining ethnic variation in the transcriptome of patients with CRC-associated sepsis and its relation to survival and genetic diversity. We conducted transcriptomic profiling of CRC tumors and adjacent non-tumor tissue obtained from adult patients of Native Hawaiian and Japanese ethnicity who died from cancer-associated sepsis. We examined differential gene expression in relation to patient survival and sepsis disease etiology.
2022-09-01 | GSE198103 | GEO
Project description:1364 plasma proteome samples taken at time-of-admission to the emergency department from patients suspected of sepsis.
Used initially with the following abstract:
Sepsis is one of the leading causes of mortality in the world. Currently, the heterogeneity of sepsis makes it challenging to determine the molecular mechanisms that define the syndrome. Here, we leverage population scale proteomics to analyze a well-defined cohort of 1364 blood samples taken at time-of-admission to the emergency department from patients suspected of sepsis. We identified panels of proteins using explainable artificial intelligence that predict clinical outcomes and applied these panels to reduce high-dimensional proteomics data to a low-dimensional interpretable latent space (ILS). Using the ILS, we constructed an adaptive digital twin model that accurately predicted organ dysfunction, mortality, and early-mortality-risk patients using only data available at time-of-admission. In addition to being highly effective for investigating sepsis, this approach supports the flexible incorporation of new data and can generalize to other diseases to aid in translational research and the development of precision medicine.
2024-04-08 | MSV000094486 | MassIVE
Project description:DNA methylation is the current strategy in the field of biomarker discovery due to its prognostic efficiency. Its role in prognosis and early diagnosis has been recognized in various types of cancer. Sepsis still remains one of the major causes of neonatal mortality due to the lack of sensitive diagnostic and prognostic biomarkers. Delay in sepsis diagnosis leads to treatment difficulties and poor outcomes. In this study, we have done an epigenome wide search to identify potential markers for prognosis of neonatal sepsis which may improve the treatment strategies. Illumina 450K methylation microarray revealed that the genes involved in transendothelial leukocyte migration were differentially methylated in septic newborns compared to non-septic newborns, especially the Protocadherin Beta group. Genes like ITGB2-AS1, CCS were found to be differentially methylated significantly, which gives the hope of developing novel, potential epigenetic markers for neonatal sepsis. From this study, we conclude that DNA methylation might play crucial functions in the pathophysiology of neonatal sepsis which was obvious from the difference in methylation level among septic and non-septic babies. In future, the potentiality of these epigenetic biomarkers can be studied in large scale with appropriate techniques which will give further in depth knowledge in this context. DNA methylation analysis of three septic newborns and three non-septic newborns were performed with Illumina Infinium HumanMethylation450 BeadChip. Peripheral venous blood sample was collected from the babies during the third day of birth while taking blood for routine investigations. Non-septic babies are babies admitted to NICU and sampled for other minor ailments. Genomic DNA was extracted using QIAmp DNA Blood Mini kit (Qiagen, Hilden, Germany) and bisulfite treated using EZ DNA methylation kit (Zymoresearch, USA).
2014-06-20 | E-GEOD-58651 | biostudies-arrayexpress
Project description:Background: Preterm infants are at high risk of infection and sepsis, which is associated with arginine (ARG) deficiency. Optimal nutrition for preterm newborns suspected with infection is critical to prevent sepsis development. Citrulline (CIT) supplementation is known to prevent sepsis in adult rodents, by maintaining sufficient blood ARG levels and vascular stabilization. We hypothesized that CIT therapy improve sepsis outcomes in infected preterm newborns via CIT and ARG metabolism.Results: After infection, oral CIT supplementation led to higher mortality, blood bacterial load, and circulating and hepatic inflammation, compared with the infected controls. Intravenous CIT administration also showed increased inflammation and bacterial burdens without increased mortality. Liver transcriptomics and data from in vitro blood stimulation indicated that CIT induces enhanced immunosuppression, which may impair resistance response to bacteria at early stage of infection and later cause excessive inflammation and tissue damage. Conclusion: Early stage of CIT supplementation exacerbates sepsis severity in infected preterm pigs, likely via induced enhanced systemic immunosuppression.
2023-11-20 | GSE247865 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Late presentation of disease at the time of diagnosis is one of the major reasons for dismal prognostic outcomes for PDAC patients. Currently, there is a lack of clinical biomarkers which can be used to diagnose PDAC patients at an early resectable stage. This study performed proteomic mass spectrometry to identify novel blood-based biomarkers for early diagnosis of PDAC.
2024-03-05 | PXD046438 | Pride