Plasma proteomics and organ dysfunction in COVID-19 ARDS
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ABSTRACT:
PROVIDER: PRJNA1194117 | ENA |
REPOSITORIES: ENA
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Project description:Fatal COVID-19 is often complicated by hypoxemic respiratory failure and acute respiratory distress syndrome (ARDS). Mechanisms governing lung injury and repair in ARDS remain poorly understood because there are no biomarker-targeted therapeutics for patients with ARDS. We hypothesized that plasma proteomics may uncover unique biomarkers that correlate with disease severity in COVID-19 ARDS. We analyzed the circulating plasma proteome from 32 patients with ARDS and COVID-19 using an aptamer-based platform, which measures 7289 proteins, and correlated protein measurements with sequential organ failure assessment (SOFA) scores at 2 time points (Days 1 and 7 following ICU admission). We compared differential protein abundance and SOFA scores at each individual time point and identified 119 proteins at Day 1 and 46 proteins at Day 7 that correlated with patient SOFA scores. We modeled the relationship between dynamic protein abundance and changes in SOFA score between Days 1 and 7 and identified 39 proteins that significantly correlated with changes in SOFA score. Using Ingenuity Pathway Analysis, we identified increased ephrin signaling and acute phase response signaling correlated with increased SOFA scores over time, while pathways related to pulmonary fibrosis signaling and wound healing had an inverse relationship with SOFA scores between Days 1 and 7. These findings suggest that persistent inflammation may drive worsened disease severity, while repair processes correlate with improvements in organ dysfunction over time. This approach is generalizable to more diverse ARDS cohorts for identification of protein biomarkers and disease mechanisms as we strive towards targeted therapies in ARDS.
2025-04-09 | GSE283501 | GEO
Project description:Background: COVID-19 has infected more than 100-million worldwide. Children appear less susceptible to COVID-19 and present with milder symptoms. Cases of children with COVID-19 developing clinical features of Kawasaki-disease have been described. Methods: We utilised SWATH-MS proteomics to determine the plasma proteins expressed in healthy children, children with multisystem inflammatory syndrome (MIS-C) and children with COVID-19 induced ARDS. Pathway analyses were performed to determine the affected pathways. Results: 76 proteins were differentially expressed across the groups, with 85 and 52 proteins specific to MIS-C and COVID-19 ARDS. Complement and coagulation activation were implicated in these clinical phenotypes, however there was contribution of FcGR and BCR activation in MIS-C and scavenging of heme and retinoid metabolism in COVID-19 ARDS. Conclusions: We show proteome differences in MIS-C and COVID-ARDS, although both show complement and coagulation dysregulation. The results may be helpful in developing therapeutic targets that could improve the outcomes for these children.
2022-04-06 | PXD025125 | Pride
Project description:SARS-CoV-2 is a novel coronavirus that causes acute respiratory distress syndrome (ARDS), death and long-term sequelae. Innate immune cells are critical for host defense but are also the primary drivers of ARDS. The relationships between innate cellular responses in ARDS resulting from COVID-19 compared to other causes of ARDS, such as bacterial sepsis is unclear. Moreover, the beneficial effects of dexamethasone therapy during severe COVID-19 remain speculative, but understanding the mechanistic effects could improve evidence-based therapeutic interventions. To interrogate these relationships, we developed an scRNAseq atlas that is freely accessible (biernaskielab.ca/COVID_neutrophil). We discovered that compared to bacterial ARDS, COVID-19 was associated with distinct neutrophil polarization characterized by either interferon (IFN) or prostaglandin (PG) active states. Neutrophils from bacterial ARDS had higher expression of antibacterial molecules such as PLAC8 and CD83. Dexamethasone therapy in COVID patients rapidly altered the IFNactive state, downregulated interferon responsive genes, and activated IL1R2+ve neutrophils. Dexamethasone also induced the emergence of immature neutrophils expressing immunosuppressive molecules ARG1 and ANXA1, which were not present in healthy controls. Moreover, dexamethasone remodeled global cellular interactions by changing neutrophils from information receivers into information providers. Importantly, male patients had higher proportions of IFNactive neutrophils and a greater degree of steroid-induced immature neutrophil expansion. Indeed, the highest proportion of IFNactive neutrophils was associated with mortality. These results define neutrophil states unique to COVID-19 when contextualized to other life-threatening infections, thereby enhancing the relevance of our findings at the bedside. Furthermore, the molecular benefits of dexamethasone therapy are also defined. The identified molecular pathways can now be targeted to develop improved therapeutics.
2021-10-05 | PXD028429 | Pride
Project description:Fourteen percent of SARS-CoV-2-infected individuals suffer multi-organ dysfunction and are unable to resume employment for >2 years post-acute COVID-19. Such "long COVID" cases have been linked to SARS-CoV-2 reservoirs and sustained complement activation. We examined the effects of lectin complement pathway MASP2 inhibitor narsoplimab on long COVID patient plasma-driven microvascular endothelial cell (MVEC) injury, comparing results to clinical outcome, plasma proteomics, and MASP2 expression. MASP2 plasma levels were 12.5-fold higher and MASP2 pulmonary deposition greater in long COVID vs. severe acute COVID-19. MVEC were exposed to long COVID plasmas +/- narsoplimab and caspase 8, a marker of cell activation and apoptosis linked to acute COVID-19 pathology, assessed. Narsoplimab suppressed caspase 8 induction. RNAseq identified pathways associated with this activity in long COVID, components of which were reflected by plasma proteomics. Our data, in the context of an early clinical trial in acute COVID-19, recommend exploration of narsoplimab in long COVID-19.
2026-08-17 | GSE343379 | GEO
Project description:While critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate immune dynamics during COVID-19 ARDS, compared to ARDS from other respiratory pathogens, is unclear. Moreover, mechanisms underlying beneficial effects of dexamethasone during severe COVID-19 remain elusive. Using scRNA-seq and plasma proteomics, we discovered that compared to bacterial ARDS, COVID-19 was associated with expansion of distinct neutrophil states characterized by interferon (IFN) and prostaglandin (PG) signalling. Dexamethasone during severe COVID-19 depleted circulating neutrophils, altered IFNactive neutrophils, downregulated interferon-stimulated gene, and activated IL1R2+ve neutrophils. Dexamethasone also expanded immunosuppressive immature neutrophils and remodeled cellular interactions by changing neutrophils from information receivers into information providers. Male patients had higher proportions of IFNactive neutrophils, preferential steroid-induced immature neutrophil expansion, and possibly different effects on outcome. Our single-cell atlas (www.biernaskielab.ca/COVID_neutrophil) defines COVID-19-enriched neutrophil states and molecular mechanisms of dexamethasone action to develop targeted immunotherapies for severe COVID-19.
2021-10-05 | GSE157789 | GEO
Project description:The acute respiratory distress syndrome (ARDS) is a common complications of severe COVID-19 and contributes to patient morbidity and mortality. ARDS is a heterogeneous syndrome caused by various insults, and results in acute hypoxemic respiratory failure. Patients with ARDS from COVID-19 may represent a subgroup of ARDS patients with distinct molecular profiles that drive disease outcomes. Here, we hypothesized that longitudinal transcriptomic analysis may identify distinct dynamic pathobiological pathways during COVID-19 ARDS. We identified a patient cohort from an existing ICU biorepository and established three groups for comparison: 1) patients with COVID-19 ARDS that survived hospitalization (COVID survivors, n = 4), 2) patients with COVID-19 ARDS that did not survive hospitalization (COVID non-survivors, n = 5), and 3) patients with ARDS from other causes as a control group (ARDS controls, n = 4). RNA was extracted from peripheral blood mononuclear cells (PBMCs) at 4 time points (Days 1, 3, 7, and 10 following ICU admission) and prepared for RNA sequencing with rRNA depletion and library generation for Illumina. An Illumina NovaSeq X Plus instrument was used to generate 150 base pair paired-end reads, which were aligned to the hg GRCh38.96 reference genome using HiSAT2. Differential expression analysis was performed with DESeq2.
2024-07-29 | GSE273149 | GEO
Project description:We compared differential gene expression in tracheal aspirates collected mechanically ventilated subjects with COVID-19 ARDS to gene expression in tracheal aspirates from: 1) subjects with ARDS from other casues and 2) mechanically ventilated controls without evidence of pulmonary disease.
2020-12-18 | GSE163426 | GEO
Project description:Acute respiratory distress syndrome (ARDS) is a severe critical condition with a high mortality that is currently in focus given that it is associated with mortality caused by coronavirus induced disease 2019 (COVID-19). Neutrophils play a key role in the lung injury characteristic of non-COVID-19 ARDS and there is also accumulating evidence of neutrophil mediated lung injury in patients who succumb to infection with SARS-CoV-2. We undertook a functional proteomic and metabolomic survey of circulating neutrophil populations, comparing patients with COVID-19 ARDS and non-COVID-19 ARDS to understand the molecular basis of neutrophil dysregulation. Expansion of the circulating neutrophil compartment and the presence of activated low and normal density mature and immature neutrophil populations occurs in ARDS, irrespective of cause. Release of neutrophil granule proteins, neutrophil activation of the clotting cascade and upregulation of the Mac-1 platelet binding complex with formation of neutrophil platelet aggregates is exaggerated in COVID-19 ARDS. Importantly, activation of components of the neutrophil type I interferon responses is seen in ARDS following infection with SARS-CoV-2, with associated rewiring of neutrophil metabolism to promote glutamine utilisation, and the upregulation of antigen processing and presentation. Whilst dexamethasone treatment constricts the immature low density neutrophil population it does not impact upon prothrombotic hyperinflammatory neutrophil signatures.
2021-02-03 | PXD023834 | Pride
Project description:Rationale COVID-19 can cause ARDS, a life-threatening condition that requires long-term ventilation. Neutrophil activation is a key mediator of lung injury in ARDS. However, the relationship between peripheral neutrophil RNA expression at the time of severe illness and 28-day ventilator weaning has not yet been clarified. Objectives To clarify the relationship with 28-day ventilator weaning and whole blood RNA sequencing analysis in COVID-19 patients. Moreover, single-cell RNA-seq was performed on neutrophils to analyze changes in gene expression levels for each fraction. Methods Bulk sequencing was performed using whole blood from 28 COVID-19 ARDS patients (9 in the non-ventilator weaning group and 19 in the ventilator weaning group) and 16 healthy controls. Next, single-cell RNA-seq was performed on neutrophils isolated from peripheral blood of 5 COVID-19 ARDS patients (3 in the non-ventilator weaning group and 2 in the ventilator weaning group) and 6 healthy individuals. Measurements and Main Results Although there was no clear difference between the non-ventilator weaning group and the ventilator weaning group in bulk RNA-seq using whole blood, the result of single-cell RNA-seq revealed clear differences between the non-ventilator weaning group, the ventilator weaning group, and healthy individuals. Conclusions Our study suggests that gene expression in neutrophils at the time of severe illness in COVID-19 ARDS patients may be associated with 28-day ventilator weaning.
2025-12-04 | GSE234902 | GEO
Project description:Rationale COVID-19 can cause ARDS, a life-threatening condition that requires long-term ventilation. Neutrophil activation is a key mediator of lung injury in ARDS. However, the relationship between peripheral neutrophil RNA expression at the time of severe illness and 28-day ventilator weaning has not yet been clarified. Objectives To clarify the relationship with 28-day ventilator weaning and whole blood RNA sequencing analysis in COVID-19 patients. Moreover, single-cell RNA-seq was performed on neutrophils to analyze changes in gene expression levels for each fraction. Methods Bulk sequencing was performed using whole blood from 28 COVID-19 ARDS patients (9 in the non-ventilator weaning group and 19 in the ventilator weaning group) and 16 healthy controls. Next, single-cell RNA-seq was performed on neutrophils isolated from peripheral blood of 5 COVID-19 ARDS patients (3 in the non-ventilator weaning group and 2 in the ventilator weaning group) and 6 healthy individuals. Measurements and Main Results Although there was no clear difference between the non-ventilator weaning group and the ventilator weaning group in bulk RNA-seq using whole blood, the result of single-cell RNA-seq revealed clear differences between the non-ventilator weaning group, the ventilator weaning group, and healthy individuals. Conclusions Our study suggests that gene expression in neutrophils at the time of severe illness in COVID-19 ARDS patients may be associated with 28-day ventilator weaning.
2025-12-04 | GSE234903 | GEO