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Nucleic acid biomarkers of immune response and cell and tissue damage in children with COVID-19 and MIS-C [wb RNA]

ABSTRACT: Differential host responses in coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in children (MIS-C) remain poorly characterized. Here we use next-generation sequencing to longitudinally analyze blood samples from pediatric patients with acute COVID-19 (n=70) or MIS-C (n=141) across three hospitals. Profiling of plasma cell-free nucleic acids uncovers distinct signatures of cell injury and death between COVID-19 and MIS-C, with increased multi-organ involvement in MIS-C encompassing diverse cell types including endothelial and neuronal cells, and an enrichment of pyroptosis related genes. Whole blood RNA profiling reveals upregulation of similar pro-inflammatory pathways in COVID-19 and MIS-C, but also MIS-C specific downregulation of T cell-associated pathways. Profiling of plasma cell-free RNA and whole blood RNA in paired samples yields different yet complementary signatures for each disease state. Our work provides a systems-level view of immune responses and tissue damage in COVID-19 and MIS-C and informs the future development of new disease biomarkers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE225220 | GEO | 2023/06/04

REPOSITORIES: GEO

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Nucleic acid biomarkers of immune response and cell and tissue damage in children with COVID-19 and MIS-C [cf DNA]

Project description:Differential host responses in coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in children (MIS-C) remain poorly characterized. Here we use next-generation sequencing to longitudinally analyze blood samples from pediatric patients with acute COVID-19 (n=70) or MIS-C (n=141) across three hospitals. Profiling of plasma cell-free nucleic acids uncovers distinct signatures of cell injury and death between COVID-19 and MIS-C, with increased multi-organ involvement in MIS-C encompassing diverse cell types including endothelial and neuronal cells, and an enrichment of pyroptosis related genes. Whole blood RNA profiling reveals upregulation of similar pro-inflammatory pathways in COVID-19 and MIS-C, but also MIS-C specific downregulation of T cell-associated pathways. Profiling of plasma cell-free RNA and whole blood RNA in paired samples yields different yet complementary signatures for each disease state. Our work provides a systems-level view of immune responses and tissue damage in COVID-19 and MIS-C and informs the future development of new disease biomarkers.

2023-06-04 | GSE225222 | GEO

Nucleic acid biomarkers of immune response and cell and tissue damage in children with COVID-19 and MIS-C [cf RNA]

2023-06-04 | GSE225221 | GEO

The innate and adaptive immune landscape of SARS-CoV-2-associated multisystem inflammatory syndrome in children (MIS-C) from acute disease to recovery

Project description:Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Deep immune profiling showed acute MIS-C patients had highly activated neutrophils, classical monocytes and memory CD8+ T-cells; increased frequencies of B-cell plasmablasts and double-negative B-cells. Post treatment samples from the same patients, taken when symptoms were resolving, identified recovery-associated immune features including CD163+ monocytes, emergence of a new population of immature neutrophils and, in some patients, a transient increase in arginase. Plasma profiling identified multiple features shared by MIS-C, Kawasaki Disease and COVID-19 and that therapeutic inhibition of IL6 may be preferable to IL1 or TNF-a. We identified potential new mechanisms of action for IVIG, the most commonly used drug to treat MIS-C. Finally, we showed systemic complement activation with high plasma C5b-9 levels is common in MIS-C, suggesting complement inhibitors could be used to treat the disease.

2021-09-10 | GSE183716 | GEO

Pathophysiological pathway differences in children who present with COVID-19 ARDS compared to COVID -19 induced MIS-C

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

Single cell RNA sequencing and TCR repertoire analysis of MIS-C affected patients versus healthy controls and severe adult COVID-19

Project description:In rare instances, pediatric SARS-CoV2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with that of severe COVID-19. MIS-C does not result in pneumocyte damage but is associated with vascular endothelitis, gastrointestinal epithelial injury and endotoxemia. In MIS-C, IFN dominates the inflammatory signature in contrast to type I interferons in severe COVID-19. While HLA-DRlo classical monocytes dominate severe COVID-19, patrolling monocyte activation characterize MIS-C. TIM-3 expression on activated CD4/CD8  T cells and on CD57+ NK cells is a distinctive MIS-C feature. In all MIS-C patients, single cell TCR profiling demonstrates a skewed TCR repertoire enriched for TRBV11-2 and a superantigenic signature which is absent in severe COVID-19. Using NicheNet, we confirm IFN as a central cytokine in the communication between activated T cells, NK cells and patrolling monocytes. Rapid normalization of IFN, TIM-3 loss on T cells and patrolling monocytes contraction upon treatment highlight their potential role in MIS-C immunopathogenesis.

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Neutrophil profiles of pediatric COVID-19 and multisystem inflammatory syndrome in children

Project description:Multisystem Inflammatory Syndrome in Children (MIS-C) is a delayed-onset, COVID-19-related hyperinflammatory illness characterized by SARS-CoV-2 antigenemia, cytokine storm, and immune dysregulation. In severe COVID-19, neutrophil activation is central to hyperinflammatory complications, yet the role of neutrophils in MIS-C is undefined. Here, we collect blood from 152 children: 31 cases of MIS-C, 43 cases of acute pediatric COVID-19, and 78 pediatric controls. We find that MIS-C neutrophils display a granulocytic myeloid-derived suppressor cell (G-MDSC) signature with highly altered metabolism, distinct from the neutrophil interferon-stimulated gene (ISG) response we observe in pediatric COVID-19. Moreover, we observe extensive spontaneous neutrophil extracellular trap (NET) formation in MIS-C, and we identify neutrophil activation and degranulation signatures. Mechanistically, we determine that SARS-CoV-2 immune complexes are sufficient to trigger NETosis. Our findings suggest that the hyperinflammatory presentation during MIS-C could be mechanistically linked to persistent SARS-CoV-2 antigenemia, driven by uncontrolled neutrophil activation and NET release in the vasculature.

2022-11-05 | GSE217370 | GEO

Biologic correlates of COVID-19 resolution using single cell RNA sequecing

Project description:We report a case of full resolution of severe COVID-19 due to convalescent plasma transfusion. Following transfusion, the patient showed fever remission, improved respiratory status, and rapidly decreased viral burden in respiratory fluids and SARS-CoV-2 RNAemia. Longitudinal single-cell transcriptomics of peripheral blood cells conducted prior to and at multiple times after convalescent plasma transfusion identified the key biological processes associated with the transition from severe disease to disease-free state. This included post-transfusion disappearance of a subset of monocytes characterized by hyperactivated Interferon responses and decreased TNF-α signaling.

2022-04-18 | GSE200896 | GEO

Longitudinal characterization of circulating neutrophils uncovers phenotypes associated with severity in hospitalized COVID-19 patients

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

An AI-guided invariant signature places MIS-C with Kawasaki disease in a continuum of host immune responses

Project description:A significant surge in cases of multisystem inflammatory syndrome in children (MIS-C, also called Pediatric Inflammatory Multisystem Syndrome - PIMS) has been observed amidst the COVID-19 pandemic. MIS-C shares many clinical features with Kawasaki disease (KD), although clinical course and outcomes are divergent. We analyzed whole blood RNA sequences, serum cytokines, and formalin fixed heart tissues from these patients using a computational toolbox of two gene signatures, i.e., viral pandemic (ViP), and a subset of it called, severe (s)ViP signatures that were developed in the context of SARS-CoV-2 infection in COVID-19 and a 13-transcript signature previously demonstrated to be diagnostic for KD. Our analyses revealed that KD and MIS-C are on the same continuum of the host immune response as COVID-19 but diverge with two different cardiac phenotypes. The ViP signatures helped unravel the nature of the host immune response (IL15-centric) in MIS-C and KD, reveal unique targetable cytokine pathways in MIS-C, place MIS-C farther along in the spectrum in severity compared to KD and pinpoint key clinical (reduced cardiac function) and laboratory (thrombocytopenia and eosinopenia) parameters that can be useful to track severity.

2022-03-20 | GSE178491 | GEO

Elevated Myl9 reflects the Myl9-containing microthrombi in SARS-CoV-2-induced exudative vasculitis and predicts COVID-19 severity

Project description:The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by SARS-CoV-2 infection-triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1 (THBS-1)-expressing non-canonical monocytes and the formation of Myosin light chain 9 (Myl9)-containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.

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