IDENTIFICATION OF BIOMARKERS OF RESPONSE TO IFNG DURING ENDOTOXIN TOLERANCE: APPLICATION TO SEPTIC SHOCK
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE46914 | GEO | 2013/07/31
SECONDARY ACCESSION(S): PRJNA203018
REPOSITORIES: GEO
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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:There is currently no reliable tool available to measure immune dysfunction in septic patients in the clinical setting. This proof-of-concept study assesses the potential of gene expression profiling of whole blood as a tool to monitor immune dysfunction in critically ill septic patients. Whole blood samples were collected daily for up to 5 days from patients admitted to the intensive care unit with sepsis. RNA isolated from whole blood samples was assayed on Illumina HT-12 gene expression microarrays consisting of 48,804 probes. Microarray analysis identified 3677 genes as differentially expressed across 5 days between septic patients and healthy controls. Of the 3677 genes, biological pathway analysis identified 86 genes significantly down-regulated in the sepsis patients were present in pathways relating to immune response. These 86 genes correspond to known immune pathways implicated in sepsis including lymphocyte depletion, reduced T lymphocyte activation and deficient antigen presentation. Furthermore, expression levels of these genes correlated with clinical severity, with a significantly greater degree of down-regulation found in non-survivors compared to survivors. The results show that whole blood gene-expression analysis can capture systemic immune dysfunctions in septic patients. Our study provides an experimental basis to support further study on the use of a gene expression based assay, to assess immunosuppression and guide immunotherapy in future clinical trials. Daily PAXgene samples for up to 5 days for sepsis survivors (n=26), sepsis nonsurvivors (n=9), and healthy controls (n=18).
2014-02-04 | E-GEOD-54514 | biostudies-arrayexpress
Project description:Background: Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. To date, no biomarker has shown sufficient evidence and ease of application in clinical routine to monitor the complexity of the sepsis-related immune alterations. Multiple levels of interaction of human endogenous retroviruses (HERVs) with the immune response led us to hypothesize that they may be relevant candidates both to contribute to the physiopathology of sepsis and to be part of a molecular signature. In this study, we used a recently described high-density microarray which allows exploring HERVs/MaLRs transcriptome in septic shock patients. Results: About 6.9% of the HERVs/MalRs repertoire is transcribed in whole blood. Concerning the functionality of LTRs, the majority of LTRs are silent (62.9%), 7.5% of LTRs present a putative constitutive promoter or polyA functions, while 20.4% of them may shift from silent to active. Evidence was given that a subset of HERVs/MaLRs and genes were modulated in septic shock patients according to the monocyte HLA-DR (mHLA-DR) expression level measured by flow cytometry, as a proxy of immunosuppression. We then identified a large signature consisting of 193 differentially expressed HERVs/MaLRs probesets further reduced to a smaller 10 HERVs/MaLRs signature. Both signatures, validated in an independent septic shock cohort, identified two groups of patients with different severity features including clinical criteria and the CD74 and CX3CR1 sepsis severity molecular markers. Conclusion: This microarray-based approach unveiled the expression of about 87,912 distinct HERV probesets and identified 764 putative promoter LTRs and 642 putative polyA LTRs in whole blood. HERV/MaLR expression was shown to be tightly modulated in septic shock patients according to mHLA-DR expression. We identified a set of potential molecular biomarkers in septic shock patients partially overlapping immunosuppression (mHLA-DR), and the risk of Health Care associated Infections (HAI) (CD74 ratio), complementary to existing molecular markers of a sepsis patients stratification. We identified a HERV/MaLR signature discriminating patients based on their immunosuppression state and severity.
2020-03-30 | GSE121350 | GEO
Project description:Background: Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. To date, no biomarker has shown sufficient evidence and ease of application in clinical routine to monitor the complexity of the sepsis-related immune alterations. Multiple levels of interaction of human endogenous retroviruses (HERVs) with the immune response led us to hypothesize that they may be relevant candidates both to contribute to the physiopathology of sepsis and to be part of a molecular signature. In this study, we used a recently described high-density microarray which allows exploring HERVs/MaLRs transcriptome in septic shock patients. Results: About 6.9% of the HERVs/MalRs repertoire is transcribed in whole blood. Concerning the functionality of LTRs, the majority of LTRs are silent (62.9%), 7.5% of LTRs present a putative constitutive promoter or polyA functions, while 20.4% of them may shift from silent to active. Evidence was given that a subset of HERVs/MaLRs and genes were modulated in septic shock patients according to the monocyte HLA-DR (mHLA-DR) expression level measured by flow cytometry, as a proxy of immunosuppression. We then identified a large signature consisting of 193 differentially expressed HERVs/MaLRs probesets further reduced to a smaller 10 HERVs/MaLRs signature. Both signatures, validated in an independent septic shock cohort, identified two groups of patients with different severity features including clinical criteria and the CD74 and CX3CR1 sepsis severity molecular markers. Conclusion: This microarray-based approach unveiled the expression of about 87,912 distinct HERV probesets and identified 764 putative promoter LTRs and 642 putative polyA LTRs in whole blood. HERV/MaLR expression was shown to be tightly modulated in septic shock patients according to mHLA-DR expression. We identified a set of potential molecular biomarkers in septic shock patients partially overlapping immunosuppression (mHLA-DR), and the risk of Health Care associated Infections (HAI) (CD74 ratio), complementary to existing molecular markers of a sepsis patients stratification. We identified a HERV/MaLR signature discriminating patients based on their immunosuppression state and severity.
2020-03-30 | GSE121349 | GEO
Project description:Extracellular cold-inducible RNA-binding protein (eCIRP) is a key mediator of severity and mortality in sepsis. We found that stimulation of mouse bone marrow–derived neutrophils (BMDNs) with eCIRP generated a distinct neutrophil subpopulation, characterized by cell surface markers of both antigen-presenting cells and aged neutrophils as well as expression of IL-12, which we named antigen-presenting aged neutrophils (APANs). The frequency of APANs was significantly increased in the blood, spleen, and lungs of WT mice subjected to cecal ligation and puncture–induced sepsis but not in CIRP–/– mice. Patients with sepsis had a significant increase in circulating APAN counts compared with healthy individuals. Compared with non–APAN-transferred mice, APAN-transferred septic mice had increased serum levels of injury and inflammatory markers, exacerbated acute lung injury (ALI), and worsened survival. APANs and CD4+ T cells colocalized in the spleen, suggesting an immune interaction between these cells. APANs cocultured with CD4+ T cells significantly induced the release of IFN-γ via IL-12. BMDNs stimulated with eCIRP and IFN-γ underwent hyper-NETosis. Stimulating human peripheral blood neutrophils with eCIRP also induced APANs, and stimulating human neutrophils with eCIRP and IFN-γ caused hyper-NETosis. Thus, eCIRP released during sepsis induced APANs to aggravate ALI and worsen the survival of septic animals via CD4+ T cell activation, Th1 polarization, and IFN-γ–mediated hyper-NETosis.
2023-09-27 | GSE228482 | GEO
Project description:Background: Severe septic syndromes deeply impair innate and adaptive immunity. While neutrophils represent the first line of defense against infection, little is known about their phenotype and functions during sepsis-induced immunosuppression. The objective of this study was thus to perform for the first time a global evaluation of neutrophil alterations in immunosuppressed septic patients based on phenotypic, functional and transcriptomic studies. In addition, the potential association of these parameters and deleterious outcomes was assessed. Methods: Peripheral blood was collected from 9 septic shock patients at D3-4 and D6-8 presenting with features of sepsis-induced immunosuppression and compared to 8 healthy controls. Results: In order to get on overview of potential neutrophil alterations after sepsis, we performed transcriptomic analyses on purified neutrophils from 9 septic shock patients and 8 healthy volunteers. For each time point, comparisons were made between patients and controls. Venn diagrams indicated that 364 up-regulated genes and 328 down-regulated genes were common between the two analyses (Supplementary Tables 1 and 2). Interestingly, most of the differentially expressed genes are involved in cell maturation (CD177), apoptosis (STK4, Caspase 8), cell recruitment and chemotaxis (CD44, TPST, MMP9, CREB1), and antimicrobial properties (ARG1, STOM, ADAM9, CD63, YKL40) of neutrophils. Conclusions: The aim of the current study was to perform an extensive investigation of neutrophil alterations during sepsis-induced immunosuppression through phenotypic, functional and transcriptomic studies. Notably, transcriptomic study on purified neutrophils revealed differentially expressed genes between septic patients and healthy volunteers.
2015-12-28 | GSE64457 | GEO
Project description:There is currently no reliable tool available to measure immune dysfunction in septic patients in the clinical setting. This proof-of-concept study assesses the potential of gene expression profiling of whole blood as a tool to monitor immune dysfunction in critically ill septic patients. Whole blood samples were collected daily for up to 5 days from patients admitted to the intensive care unit with sepsis. RNA isolated from whole blood samples was assayed on Illumina HT-12 gene expression microarrays consisting of 48,804 probes. Microarray analysis identified 3677 genes as differentially expressed across 5 days between septic patients and healthy controls. Of the 3677 genes, biological pathway analysis identified 86 genes significantly down-regulated in the sepsis patients were present in pathways relating to immune response. These 86 genes correspond to known immune pathways implicated in sepsis including lymphocyte depletion, reduced T lymphocyte activation and deficient antigen presentation. Furthermore, expression levels of these genes correlated with clinical severity, with a significantly greater degree of down-regulation found in non-survivors compared to survivors. The results show that whole blood gene-expression analysis can capture systemic immune dysfunctions in septic patients. Our study provides an experimental basis to support further study on the use of a gene expression based assay, to assess immunosuppression and guide immunotherapy in future clinical trials.
2014-02-04 | GSE54514 | GEO
Project description:Our experiments examined T-lymphocyte numbers and effector-functions in peritoneal contamination and infection (PCI) a mouse model of sepsis. One of our main questions was how T-lymphocytes reconstitute after sepsis-induced lymphopenia. We investigated the quantitative and qualitative recovery of T lymphocytes for 3.5 months after sepsis with or without IL-7 treatment. Sepsis is an immunological dysfunction against pathogens leading to inflammation with massive cytokine production. Simultaneously immunosuppression occurs e.g. lymphopenia, which is a hallmark of sepsis. The resulting immunosuppression is associated with secondary infections, which are often lethal. Moreover sepsis-survivors are burdened with increased morbidity and mortality for several years after the sepsis episode. The duration and clinical consequences of sepsis induced-immunosuppression are currently unknown. More than 50% of T-cells undergo apoptosis shortly after sepsis-induction. However, 8 days after sepsis onset, surviving mice present normal lymphocyte counts. Theoretically, T-cells could reconstitute in two different ways. Firstly, the diminished pool of T-cells is replenished by newly in thymus produced T-cells with new diverse T-cell-receptors (TCRs). Alternatively, remaining T-cells start to proliferate until reaching normal cell count. If this was the case all divided cells shared the same TCRs as primary cells. This could lead to a narrowed TCR diversity within a quantitative normalized T-cell pool and would be an explanation for the long-lasting immune incompetence. To address the question how T-cells recover from lymphopenia we applied next generation sequencing (NGS) to analyse TCR diversity in septic and healthy mice. One group of septic mice received Interleukin-7 (IL-7), an interleukin which regulates T-cell homeostasis and is a promising therapeutically approach for septic patients. 50000 sequences per mouse were analyzed and the three different groups (controls, sepsis, sepsis + IL-7 treatment) compared regarding their diversity. The sequenced raw data (fastq) are uploaded in this library.
2019-10-02 | E-MTAB-7483 | biostudies-arrayexpress
Project description:Sepsis patients experience a complex interplay of host pro- and anti-inflammatory processes which can compromise outcome. Even taking the latest clinical and scientific research data into account, the immunosuppressive events occurring during a septic episode are incompletely understood. Moreover, there is a lack of data on the way epigenetics can modulate immunosuppression, which in turn affects patient survival. To advance current understanding of the mechanisms underlying immunosuppression, in this study we explored DNA methylation changes using the Infinium MethylationEPIC v1.0 BeadChip Kit in leukocytes from patients suffering from sepsis, septic shock, and critically ill patients as controls, within the first 24 h after admission in the Intensive Care Unit of a tertiary hospital. The top 100 differentially methylated positions (DMPs) between septic shock and critically ill patients enabled us to clearly distinguish between the 3 groups of patients. Interestingly, the top 6,657 DMPs were associated with organ dysfunction and lactate levels. Two different analysis approaches (based on the use of DMRcate and mCSEA) comparing septic shock and critically ill patients revealed a total of 1,256 differentially methylated regions (DMRs) involved in critical immune system-related pathways. Among the individual genes exhibiting significant differential methylation, IL10, TREM1, IL1B, and TNFAIP8 showed the largest methylation differences among the different groups when analyzing their methylation levels by DNA bisulfite pyrosequencing. Our findings indicate that DNA methylation profile undergoes the most substantial changes in patients with septic shock, and that these changes are linked to disease severity. Importantly, IL10 and S100A8, which are closely related to immunosuppression, were hypomethylated in septic shock patients.
2023-12-18 | GSE247524 | GEO
Project description:Sepsis patients are at increased risk for hospital-acquired pulmonary infections, potentially due to post-septic immunosuppression known as the compensatory anti-inflammatory response syndrome (CARS). CARS has been attributed to leukocyte dysfunction, with an unclear role for endothelial cells. The pulmonary circulation is lined by an endothelial glycocalyx, a heparan sulfate-rich layer essential to pulmonary homeostasis. Heparan sulfate degradation occurs early in sepsis, leading to lung injury. Endothelial synthesis of new heparan sulfates subsequently allows for glycocalyx reconstitution and endothelial recovery. We hypothesized that remodeling of the reconstituted endothelial glycocalyx, mediated by alterations in the endothelial machinery responsible for heparan sulfate synthesis, contributes to CARS. Our experimental animal model of CARS recapitulated post-septic immunosuppression, coincidentally with structural remodeling of endothelial glycocalyx heparan sulfate. We used microarray to identify which heparan sulfate modifying enzyme is responsible for the remodeling of post-septic reconstituted glycocalyx, characterized with enrichment of heparan sulfate disaccharides sulfated at the 6-O position of glucosamine.
2019-04-14 | GSE129775 | GEO