Specialized interferon ligand action in COVID19

The impacts of IFN signaling on COVID19 pathology are multiple, with protective and harmful effects being documented. We report here a multi-omics investigation of IFN signaling in hospitalized COVID19 patients, defining the biosignatures associated with varying levels of 12 different IFN ligands. Previously we showed that seroconversion associates with decreased production of select IFN ligands (Galbraith et al, 2021). We show now that the antiviral transcriptional response in circulating immune cells is strongly associated with a specific subset of ligands, most prominently IFNA2 and IFNG. In contrast, proteomics signatures indicative of endothelial damage associate with levels of IFNB and IFNA6. Differential IFN ligand production is linked to distinct constellations of circulating immune cells. Lastly, IFN ligands associate differentially with activation of the kynurenine pathway, dysregulated fatty acid metabolism, and altered central carbon metabolism. Altogether, these results reveal specialized IFN ligand action in COVID19, with potential diagnostic and therapeutic implications. IMPACT STATEMENTAnalysis of multi-omics signatures associated with 12 different IFN ligands reveals their specialized action in COVID19.

The COVIDome Explorer Researcher Portal

COVID-19 pathology involves dysregulation of diverse molecular, cellular, and physiological processes. In order to expedite integrated and collaborative COVID-19 research, we completed multi-omics analysis of hospitalized COVID-19 patients including matched analysis of the whole blood transcriptome, plasma proteomics with two complementary platforms, cytokine profiling, plasma and red blood cell metabolomics, deep immune cell phenotyping by mass cytometry, and clinical data annotation. We refer to this multidimensional dataset as the COVIDome. We then created the COVIDome Explorer, an online researcher portal where the data can be analyzed and visualized in real time. We illustrate here the use of the COVIDome dataset through a multi-omics analysis of biosignatures associated with C-reactive protein (CRP), an established marker of poor prognosis in COVID-19, revealing associations between CRP levels and damage-associated molecular patterns, depletion of protective serpins, and mitochondrial metabolism dysregulation. We expect that the COVIDome Explorer will rapidly accelerate data sharing, hypothesis testing, and discoveries worldwide.

Seroconversion stages COVID19 into distinct pathophysiological states

COVID19 is a heterogeneous medical condition involving a suite of 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. Seronegative COVID19 patients harbor hyperactive T cells and NK cells, high levels of IFN alpha, gamma and lambda ligands, markers of systemic complement activation, neutropenia, lymphopenia and thrombocytopenia. In seropositive patients, all of these processes are attenuated, observing instead increases in B cell subsets, emergency hematopoiesis, increased markers of platelet activation, 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.

JAK1 inhibition blocks lethal sterile immune responses:implications for COVID-19 therapy

Cytokine storms are drivers of pathology and mortality in myriad viral infections affecting the human population. In SARS-CoV-2-infected patients, the strength of the cytokine storm has been associated with increased risk of acute respiratory distress syndrome, myocardial damage, and death. However, the therapeutic value of attenuating the cytokine storm in COVID-19 remains to be defined. Here, we report results obtained using a novel mouse model of lethal sterile anti-viral immune responses. Using a mouse model of Down syndrome (DS) with a segmental duplication of a genomic region encoding four of the six interferon receptor genes (Ifnrs), we demonstrate that these animals overexpress Ifnrs and are hypersensitive to IFN stimulation. When challenged with viral mimetics that activate Toll-like receptor signaling and IFN anti-viral responses, these animals overproduce key cytokines, show exacerbated liver pathology, rapidly lose weight, and die. Importantly, the lethal immune hypersensitivity, accompanying cytokine storm, and liver hyperinflammation are blocked by treatment with a JAK1-specific inhibitor. Therefore, these results point to JAK1 inhibition as a potential strategy for attenuating the cytokine storm and consequent organ failure during overdrive immune responses. Additionally, these results indicate that people with DS, who carry an extra copy of the IFNR gene cluster encoded on chromosome 21, should be considered at high risk during the COVID-19 pandemic. One Sentence SummaryInhibition of the JAK1 kinase prevents pathology and mortality caused by a rampant innate immune response in mice.