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Proc Natl Acad Sci U S A ; 119(11)2022 03 15.
Article in English | MEDLINE | ID: covidwho-1713294


The impacts of interferon (IFN) signaling on COVID-19 pathology are multiple, with both protective and harmful effects being documented. We report here a multiomics investigation of systemic IFN signaling in hospitalized COVID-19 patients, defining the multiomics biosignatures associated with varying levels of 12 different type I, II, and III IFNs. The antiviral transcriptional response in circulating immune cells is strongly associated with a specific subset of IFNs, most prominently IFNA2 and IFNG. In contrast, proteomics signatures indicative of endothelial damage and platelet activation associate with high levels of IFNB1 and IFNA6. Seroconversion and time since hospitalization associate with a significant decrease in a specific subset of IFNs. Additionally, differential IFN subtype production is linked to distinct constellations of circulating myeloid and lymphoid immune cell types. Each IFN has a unique metabolic signature, with IFNG being the most associated with activation of the kynurenine pathway. IFNs also show differential relationships with clinical markers of poor prognosis and disease severity. For example, whereas IFNG has the strongest association with C-reactive protein and other immune markers of poor prognosis, IFNB1 associates with increased neutrophil to lymphocyte ratio, a marker of late severe disease. Altogether, these results reveal specialized IFN action in COVID-19, with potential diagnostic and therapeutic implications.

Blood/metabolism , COVID-19/immunology , Interferons/blood , Proteome , Transcriptome , COVID-19/blood , Case-Control Studies , Datasets as Topic , Humans , Inpatients
Elife ; 102021 03 16.
Article in English | MEDLINE | ID: covidwho-1136623


COVID19 is a heterogeneous medical condition involving diverse underlying pathophysiological processes including hyperinflammation, endothelial damage, thrombotic microangiopathy, and end-organ damage. Limited knowledge about the molecular mechanisms driving these processes and lack of staging biomarkers hamper the ability to stratify patients for targeted therapeutics. We report here the results of a cross-sectional multi-omics analysis of hospitalized COVID19 patients revealing that seroconversion status associates with distinct underlying pathophysiological states. Low antibody titers associate with hyperactive T cells and NK cells, high levels of IFN alpha, gamma and lambda ligands, markers of systemic complement activation, and depletion of lymphocytes, neutrophils, and platelets. Upon seroconversion, all of these processes are attenuated, observing instead increases in B cell subsets, emergency hematopoiesis, increased D-dimer, and hypoalbuminemia. We propose that seroconversion status could potentially be used as a biosignature to stratify patients for therapeutic intervention and to inform analysis of clinical trial results in heterogenous patient populations.

COVID-19/epidemiology , COVID-19/virology , SARS-CoV-2 , Seroconversion , Biomarkers , COVID-19/immunology , COVID-19/metabolism , Comorbidity , Complement Activation/immunology , Complement System Proteins/immunology , Hematopoiesis , Homeostasis , Hospitalization , Humans , Hypoalbuminemia , Interferons/metabolism , Models, Biological , Seroepidemiologic Studies , Signal Transduction
Cell Rep ; 33(7): 108407, 2020 11 17.
Article in English | MEDLINE | ID: covidwho-927290


Individuals with Down syndrome (DS; trisomy 21) display hyperactivation of interferon (IFN) signaling and chronic inflammation, which could potentially be explained by the extra copy of four IFN receptor (IFNR) genes encoded on chromosome 21. However, the clinical effects of IFN hyperactivity in DS remain undefined. Here, we report that a commonly used mouse model of DS overexpresses IFNR genes and shows hypersensitivity to IFN ligands in diverse immune cell types. When treated repeatedly with a TLR3 agonist to induce chronic inflammation, these animals overexpress key IFN-stimulated genes, induce cytokine production, exhibit liver pathology, and undergo rapid weight loss. Importantly, the lethal immune hypersensitivity and cytokine production and the ensuing pathology are ameliorated by JAK1 inhibition. These results indicate that individuals with DS may experience harmful hyperinflammation upon IFN-inducing immune stimuli, as observed during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, pointing to JAK1 inhibition as a strategy to restore immune homeostasis in DS.

Azetidines/therapeutic use , Down Syndrome/immunology , Hypersensitivity/drug therapy , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Sulfonamides/therapeutic use , Animals , Down Syndrome/complications , Female , Hypersensitivity/etiology , Hypersensitivity/immunology , Immunity, Innate , Interferon-alpha/metabolism , Liver/immunology , Male , Mice , Mice, Inbred C57BL , Purines , Pyrazoles , Toll-Like Receptors/metabolism