Whole blood transciptome analysis in severe Covid-19 patients and healthy donors
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE171110 | GEO | 2021/05/27
REPOSITORIES: GEO
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Project description:Infection with the SARS-CoV2 virus can vary from asymptomatic, flu-like with moderate disease, to critically severe. Severe disease, termed COVID-19, involves acute respiratory deterioration that is frequently fatal. To understand the highly variable presentation, and identify biomarkers for disease severity, blood RNA from COVID-19 patient in an intensive care unit was analyzed by whole transcriptome RNA sequencing. Both SARS-CoV2 infection and the severity of COVID-19 syndrome were associated with up to 25-fold increased expression of neutrophil-related transcripts, such as neutrophil defensin 1 (DEFA1), and 3-5-fold reductions in T cell related transcripts such as the T cell receptor (TCR). The DEFA1 RNA level detected SARSCoV2 viremia with 95.5% sensitivity, when viremia was measured by ddPCR of whole blood RNA. Purified CD15+ neutrophils from COVID-19 patients were increased in abundance and showed striking increases in nuclear DNA staining by DAPI. Concurrently, they showed >10-fold higher elastase activity than normal controls, and correcting for their increased abundance, still showed 5-fold higher elastase activity per cell. Despite higher CD15+ neutrophil elastase activity, elastase activity was extremely low in plasma from the same patients. Collectively, the data supports the model that increased neutrophil and decreased T cell activity is associated with increased COVID19 severity, and suggests that blood DEFA1 RNA levels and neutrophil elastase activity, both involved in neutrophil extracellular traps (NETs), may be informative biomarkers of host immune activity after viral infection.
2021-12-04 | GSE189990 | GEO
Project description:Mechanisms of neutrophil involvement in severe COVID-19 remain incompletely understood. Here we collect longitudinal blood samples from 306 hospitalized COVID-19+ patients and 86 controls, and perform bulk RNA-sequencing of enriched neutrophils, plasma proteomics, and high-throughput antibody profiling to investigate relationships between neutrophil states and disease severity. We identify dynamic switches between 6 distinct neutrophil subtypes. At days 3 and 7 post-hospitalization, patients with severe disease display a granulocytic myeloid-derived suppressor cell-like gene expression signature, while patients with resolving disease show a neutrophil progenitor-like signature. Humoral responses are identified as potential drivers of neutrophil effector functions, with elevated SARS-CoV-2-specific IgG1-to-IgA1 ratios in plasma of severe patients who survived. In vitro experiments confirm that while patient-derived IgG antibodies induce phagocytosis in healthy donor neutrophils, IgA antibodies predominantly induce neutrophil cell death. Overall, our study demonstrates a dysregulated myelopoietic response in severe COVID-19 and a potential role for IgA-dominant responses contributing to mortality.
2022-08-28 | GSE212041 | GEO
Project description:Social creatures must attend to threat signals from conspecifics and respond appropriately, both behaviorally and physiologically. In this work, we show a threat-sensitive immune signaling that orchestrates psychological processes and is amenable to social modulation. Repeated encounters with socially-cued threats triggered neutrophil priming preferentially in males. Meningeal niche-specific neutrophil activity was correlated with attenuated defensive responses to cues. The neutrophil-specific membrane protein CD177 responded to threat-predicting social cues, and its genetic ablation abrogated male behavioral phenotypes. Neutrophil CD177 signaling facilitated optimal meningeal IFN-γ production, which blunted neural response to threatening stimuli by enhancing intrinsic GABAergic inhibition within the prelimbic cortex. Initiation of meningeal neutrophil-mediated IFN-γ signaling was sensitized by negative emotional states and governed by socially dependent androgen release. This male-biased hormone/neutrophil regulatory axis is seemingly conserved in humans. Our findings provide insights into how immune responses influence behavioral responses to threats, suggesting a possible neuroimmune basis of emotional regulation.
2024-09-30 | GSE276662 | GEO
Project description:Early diagnosis of sepsis and discrimination from SIRS is crucial for clinicians to provide appropriate care, management and treatment to critically ill patients. Here, we describe identification of transcriptional mRNA biomarkers able to identify severe systemic inflammation and differentiate Sepsis from SIRS, in adult patients within a multi-center clinical study. All patients were recruited in Intensive Care Units (ICUs) from multiple UK hospitals including 59 patients with abdominal sepsis, 84 patients with pulmonary sepsis, 42 SIRS patients with Out-of-Hospital Cardiac Arrest (OOHCA), at four time points including 30 healthy control donors. Multiple clinical parameters were measured, including SOFA score etc., with many differences observed between SIRS and sepsis groups. Differential gene expression analyses were performed using PBL mRNA microarray hybridization and data analyzed using a combination of parametric and non-parametric statistical tools. Nineteen select high-performance, differentially-expressed mRNA biomarkers were identified between control and combined SIRS/Sepsis groups (FC>20.0, p<0.05), termed ‘indicators of inflammation’ (IoI), including CD177, FAM20A and OLAH. Combinations of these were trialed. Best-performing minimal panels e.g. FAM20A/OLAH showed good accuracy for determination of severe, systemic inflammation (ROC/AUC>0.99). Twenty select entities were differentially-expressed between sepsis and SIRS (FC>2.0, p-value<0.05), termed ‘SIRS or Sepsis’ (SoS) biomarkers. Panels of biomarkers able to differentiate sepsis from SIRS were also identified and performance assessed using AUCROC. The best performing panel was CMTM5/CETP/PLA2G7/MIA/MPP3 using our dataset (AUCROC=0.9758). The IoI and SoS signatures were evaluated on other independent gene expression datasets, with some reduced performance observed, which maybe in part due to study/platform technical variation.
2024-01-08 | GSE236713 | 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:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel viral pathogen that causes a clinical disease called coronavirus disease 2019 (COVID-19). Approximately 20% of infected patients experience a severe manifestation of the disease, causing bilateral pneumonia and acute respiratory distress syndrome. Severe COVID-19 patients also have a pronounced coagulopathy with approximately 30% of patients experiencing thromboembolic complications. However, the cellular etiology driving the coagulopathy remains unknown. Here, we explore whether the prominent neutrophilia seen in severe COVID-19 patients contributes to inflammation-associated coagulation. We found in severe patients the emergence of a CD16Int low-density inflammatory band (LDIB) neutrophil population that trends over time with changes in disease status. These cells demonstrated spontaneous neutrophil extracellular trap (NET) formation, higher phagocytic capacity, enhanced cytokine production, and associated clinically with D-dimer, ferritin, and systemic IL-6 and TNF-α levels. Strikingly, LDIB neutrophils are the major immune cells within the bronchoalveolar lavage (BAL) fluid with increased CXCR3 and loss of CD44 and CD38 expression. We conclude that the LDIB subset contributes to COVID- 19-associated coagulopathy (CAC) and systemic inflammation and could be used as an adjunct clinical marker to monitor disease status and progression. Identifying patients who are trending towards LDIB crisis and implementing early, appropriate treatment could improve all-cause mortality rates for severe COVID-19 patients.
2021-07-20 | GSE154311 | GEO
Project description:BACKGROUND: Despite best supportive intensive care, the development of severe sepsis and septic shock after trauma is still associated with a high mortality rate in intensive care units (ICU). Incomplete knowledge of the pathophysiological and biochemical mechanisms that lead to perturbations of the host system is a major cause for this clinical entity. This lack of knowledge is mirrored in a delay in both diagnosis of sepsis and stratification of patients at risk. The current diagnostic and classification methods do not provide an early and reliable evidence for the development of sepsis and consequently lead to uncertainty in the classification and a delay in the initiation of an adequate therapy. Here, we present a prospective study performed with a well-defined patient cohort suffering from severe multiple trauma (n=85), in which we aimed to uncover the biological reasons why patients with multiple trauma can have dramatically different outcomes after suffering similar traumatic insults. METHODS: We used peripheral whole blood obtained with the PaxGene system at the time of admission to the ICU, i.e., 12 hours after trauma, for transcriptome analysis and monitored clinically the sequence of events from the admission to the ICU, to the very onset of sepsis and finally to the full development of multiple organ dysfunction syndrome (MODS). Study protocols and standard operating procedures (SOPs) regarding ethics, patient recruitment, logistics in sample acquisition and storage, microarray experiments, data analysis and data management have been developed and provided for a high feasibility and reproducibility of the investigations. FINDINGS: The transcriptome analysis from peripheral blood revealed a strong host response upon severe injury and demonstrated the suitability of whole blood in the PaxGene system as a surrogate marker in clinical gene expression studies. It was evident that patients who developed sepsis in the course of the disease (3-5 days after admission) showed an imbalance in the TH1/TH2 response towards a pronounced TH2 response, soon after trauma. The imbalanced TH1/TH2 shift along with inactivation of T cells, neutrophils, monocytes and macrophages might be critical factors for the initiation of a septic program seen in these patients 12 hours after trauma. INTERPRETATION: First, in this study, we provide protocols for logistics and infrastructure that can be applied generally to successfully integrate gene expression analysis studies in a clinical routine and demonstrate that by following these protocols, dedicated and reproducible results can be obtained. Second, we showed that peripheral whole blood is a suitable surrogate marker for the host response as it contains lots of “information” and is easily accessible. Third, we identified mechanisms involved in the perturbations of the immune system that lead to sepsis. Keywords: Prospective study 159 consecutive traumatized patients were included in the study upon admission to the intensive care unit (ICU), fulfilling all of the following inclusion criteria: severe injuries to at least two body regions or three major fractures, between 18 and 65 years of age, an estimated Injury Severity Score (ISS) of ?15 points after thorough assessment of injuries, <12 hours between the occurrence of the accident and the time of admission to the ICU, and at least greater than 3 days of survival. None of the patients underwent neuro- or cardiac surgery. We excluded patients with severe intracranial head injuries, coagulation abnormalities known at the day of admission to the ICU, acute renal failure, liver failure, malignant disease, or hemofiltration in the patient`s history. The Patients were divided into two groups depending on their posttraumatic course: Patients not complicatd by sepsis (Group: N) and Patients complicated by sepsis (Group: S). Using the CodeLink UniSet Human 10 K Bioarrays (GE Healthcare, Freiburg, Germany), we searched for early differences in the transcriptome of these two groups. Only whole blood samples drawn upon admission to the ICU were used for this investigation. Microarray results were validated by quantification of mRNA by TaqMan® technology. Each patient sample was hybridized in duplicate or triplicate on microarrays (label-extract technical replicate). A total of 72 arrays (36 group N, 36 group S) were subjected to microarray quality analysis. Of these, 2 arrays (0 group N, 2 group S) were excluded from the data set due to quality reasons and a final set of 70 arrays (36 group N and 34 group S) were subjected to microarray analysis. Since the eliminated 2 arrays belonged to patients with three replicates, they were treated as two replicates in the further analysis. The arrays were designated N_xx_yy_z or S_xx_yy_z, with x for the patient-ID (1,2,3,4..) and z for the technical replicate number (1,2 or 3).
2010-12-22 | E-GEOD-12624 | biostudies-arrayexpress
Project description:Rationale: Patients in the intensive care unit (ICU) are frequently exposed to unnecessary antibiotics. Markers of the host response to infection may aid pneumonia diagnosis and avoid antibiotic-induced complications. Objective: To assess the host response to suspected bacterial pneumonia through assessment of alveolar neutrophilia and transcriptomic profiling of alveolar macrophages. Methods: We determined the test characteristics of BAL neutrophilia for the diagnosis of bacterial pneumonia in 3 cohorts of mechanically ventilated patients. In one cohort, we also isolated alveolar macrophages from BAL fluid and used the transcriptome to identify signatures of bacterial pneumonia. Finally, we developed a humanized mouse model of Pseudomonas aeruginosa pneumonia to determine if pathogen-specific signatures can be identified in human alveolar macrophages. Measurements and Main Results: BAL neutrophilia was highly sensitive for bacterial pneumonia in both the retrospective (N = 851) and validation cohorts (N = 76 and N = 79) with a negative predictive value of over 90% when BAL neutrophil percentage was less than 50%. A transcriptional signature of bacterial pneumonia was present in both resident and recruited macrophages. Gene signatures from both cell types identified patients with bacterial pneumonia with test characteristics similar to BAL neutrophilia. Conclusions: A BAL neutrophil percentage of less than 50% is highly sensitive for bacterial pneumonia. Informative transcriptomic signatures can be generated from BAL fluid obtained during routine clinical care in the ICU. The identification of novel host response biomarkers is a promising approach to aid the diagnosis and treatment of pneumonia.
2018-11-06 | GSE121871 | GEO
Project description:High-resolution mass spectrometry and the parallel quantitative evaluation of thousands of proteins has been used to characterise the proteomes of peripheral blood neutrophils from >200 individuals. This work has comprehensively mapped neutrophil molecular changes associated with mild versus severe COVID19 and identified significant quantitative changes in more than 1700 proteins in neutrophils from patients hospitalised with COVID19 versus patients with non-COVID19 acute respiratory infections. The study identifies neutrophil protein signatures associated with COVID19 disease severity. The data also show that alterations in neutrophil proteomes can persist in fully recovered patients and identify distinct neutrophil proteomes in recovered versus non recovered patients. Our study provides novel insights into neutrophil responses during acute COVID-19 and reveal that altered neutrophil phenotypes persist in convalescent COVID19 infections.
2022-08-17 | PXD036082 | Pride