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Proteomic Profiling of MIS-C Patients Reveals Heterogeneity R 1 elating to Interferon 2 Gamma Dysregulation and Vascular Endothelial Dysfunction

ABSTRACT: The pathologic mechanisms causing Multisystem 38 Inflammatory Syndrome in Children (MIS-C) are not yet known; we sought to use high throughput proteomics to uncover signatures of dysregulation suggestive of pathophysiology fo this condition. MIS-C is a major complication of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic in pediatric patients. Weeks after an often mild or asymptomatic initial infection with SARS-CoV-2 children may present with a severe shock-like picture and marked inflammation. Children with MIS-C present with varying degrees of cardiovascular and hyperinflammatory symptoms. We performed a comprehensive analysis of more than 1400 proteins in the plasma proteome of children with SARS-CoV-2 and MIS-C.

INSTRUMENT(S): GENOLINK

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Blood Plasma

DISEASE(S): Severe Covid-19

SUBMITTER: Rawan Shraim

LAB HEAD: Dr. David Teachey

PROVIDER: PXD029375 | Pride | 2021-11-25

REPOSITORIES: Pride

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Multisystem inflammatory syndrome in children (MIS-C) serum proteomics

Project description:While fewer cases of severe Coronavirus Disease 2019 (COVID-19) are reported globally in children, a small proportion of SARS-CoV-2 infected children develop a novel pediatric febrile entity called multisystem inflammatory syndrome in children (MIS-C) that develops 2 to 5 weeks after initial SARS-CoV-2 exposure. MIS-C primarily effects male children and children of Hispanic or black descent. MIS-C manifests as a severe and uncontrolled inflammatory response with multiorgan involvement. A hyperinflammatory state is evidenced by clinical makers of inflammation including high levels of C-reactive protein (CRP), ferritin, and D-dimers, and an increased expression of pro-inflammatory cytokines. Children often present with persistent fever, severe gastrointestinal symptoms, cardiovascular manifestations, respiratory symptoms and neurological symptoms6-11,13. Cardiovascular manifestations include hypotension, shock, cardiac dysfunction, myocarditis and pericardial effusion. In the united states, admission to the intensive care unit occurs in approximately 58% of cases. To understand disease pathogenesis of MIS-C and proteins associated with the severe form of disease we performed proteomics analysis of serum or plasma samples. We collected serum from healthy children (SARS-CoV-2 negative, n=20), mild MIS-C (non-ICU, n=5) and severe MIS-C (ICU, n = 20) patients. MIS-C definition and diagnosis was performed according to CDC guidelines. Healthy adult serum (n = 4) was also used for reference ranges quality control and we obtained plasma samples from Kawasaki Disease (KD; n=7) patients that were recruited before the Coronavirus Disease 2019 (COVID-19) pandemic.

2021-09-29 | PXD025462 | Pride

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

A monocyte/dendritic cell molecular signature of SARS-CoV2-related multisystem inflammatory syndrome in children (MIS-C) with severe myocarditis [Bulk RNAseq]

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2021-07-13 | GSE167028 | GEO

A monocyte/dendritic cell molecular signature of SARS-CoV2-related multisystem inflammatory syndrome in children (MIS-C) with severe myocarditis [Single cell RNAseq]

2021-07-13 | GSE167029 | GEO

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Project description:While SARS-CoV-2 infection results in a mild disease course for most children, severe manifestations including respiratory failure and a Multisystem Inflammatory Syndrome in Children (MIS-C) can develop in rare cases. Here, we present a longitudinal immune profiling study of children who developed SARS-CoV-2-associated MIS-C during acute disease and following recovery, relative to children with more typical clinical manifestations of SARS-CoV-2 infection. We demonstrate distinct immune parameters associated with acute MIS-C including elevated levels of pro-inflammatory cytokines in circulation not observed in children with acute COVID-19 (non-MIS-C), aberrant expression of activation and tissue residency signatures by T cells, and expansion of T cells bearing specific TCR chains. Importantly, markers of tissue-derived T cells correlated with clinical measurements of cardiac damage suggesting key roles for T cells in the disease process. While these T cell alterations and the accompanying systemic inflammation resolved during recovery, children with prior MIS-C generated increased frequencies of functionally robust virus-specific T cells compared to children who recovered from mild disease, while both cohorts generated protective, long-lasting SARS-CoV-2-specific antibodies. Together our results reveal that the T cell response in acute MIS-C contributed to disease pathology, while also generating robust memory responses for future immune protection.

2023-04-10 | GSE213192 | GEO

Diagnosis of multisystem inflammatory syndrome in children (MIS-C) by a whole-blood transcriptional signature

Project description:Multisystem inflammatory syndrome in children (MIS-C) occurs in some children approximately 2-6 weeks following infection with SARS-CoV-2. Clinical symptoms are highly overlapping with Kawasaki disease (KD) and bacterial (DB) and viral (DV) infections, making diagnosis particularly challenging. Host whole blood transcriptomics can reveal specific combinations of host genes whose expression patterns can distinguish between disease groups of interest. We performed whole blood RNA-Sequencing of individuals with MIS-C, KD, bacterial and viral infections to identify a number of host genes that, when combined, could be used to diagnose MIS-C. This data contains processed data only. Raw data will be available via a controlled access archive.

2023-06-27 | E-MTAB-12793 | biostudies-arrayexpress

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

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

Case Report: Deep Immune Profiling Links Neutrophil and Plasmablast Dysregulation to Microvascular Damage in post-COVID-19 Multisystem Inflammatory Syndrome of Adults (MIS-A).

Project description:Despite surviving a SARS-CoV-2 infection, some individuals experience an intense post-infectious Multisystem Inflammatory Syndrome (MIS) of uncertain etiology. Children with this syndrome (MIS-C) can experience a Kawasaki-like disease, but mechanisms in adults (MIS-A) are not clearly defined. Here we utilize a deep phenotyping approach to examine immunologic responses in an individual with MIS-A. Results are contextualized to healthy, convalescent, and acute COVID-19 patients. The findings reveal systemic inflammatory changes involving novel neutrophil and B-cell subsets, autoantibodies, complement, and hypercoagulability that are linked to systemic vascular dysfunction. This deep patient profiling generates new mechanistic insight into this rare clinical entity and provides potential insight into other post-infectious syndromes.

2023-02-22 | GSE171052 | 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

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